Rifamycins – Obstacles and opportunities

Tuberculosis 90 (2010) 94e118

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Tuberculosis journal homepage: http://intl.elsevierhealth.com/journals/tube

REVIEW

Rifamycins e Obstacles and opportunities Paul A. Aristoff a, George A. Garcia b, *, Paul D. Kirchhoff b, H.D. Hollis Showalter b a b

Aristoff Consulting, LLC, Dexter, MI, United States Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 428 Church St., Ann Arbor, MI 48109-1065, United States

a r t i c l e i n f o

s u m m a r y

Article history: Received 1 December 2009 Received in revised form 2 February 2010 Accepted 2 February 2010

With nearly one-third of the global population infected by Mycobacterium tuberculosis, TB remains a major cause of death (1.7 million in 2006). TB is particularly severe in parts of Asia and Africa where it is often present in AIDS patients. Difficulties in treatment are exacerbated by the 6e9 month treatment times and numerous side effects. There is significant concern about the multi-drug-resistant (MDR) strains of TB (0.5 million MDR-TB cases worldwide in 2006). The rifamycins, long considered a mainstay of TB treatment, were a tremendous breakthrough when they were developed in the 1960's. While the rifamycins display many admirable qualities, they still have a number of shortfalls including: rapid selection of resistant mutants, hepatotoxicity, a flu-like syndrome (especially at higher doses), potent induction of cytochromes P450 (CYP) and inhibition of hepatic transporters. This review of the state-ofthe-art regarding rifamycins suggests that it is quite possible to devise improved rifamycin analogs. Studies showing the potential of shortening the duration of treatment if higher doses could be tolerated, also suggest that more potent (or less toxic) rifamycin analogs might accomplish the same end. The improved activity against rifampin-resistant strains by some analogs promises that further work in this area, especially if the information from co-crystal structures with RNA polymerase is applied, should lead to even better analogs. The extensive drugedrug interactions seen with rifampin have already been somewhat ameliorated with rifabutin and rifalazil, and the use of a CYP-induction screening assay should serve to efficiently identify even better analogs. The toxicity due to the flu-like syndrome is an issue that needs effective resolution, particularly for analogs in the rifalazil class. It would be of interest to profile rifalazil and analogs in relation to rifampin, rifapentine, and rifabutin in a variety of screens, particularly those that might relate to hypersensitivity or immunomodulatory processes. Ó 2010 Elsevier Ltd. All rights reserved.

Keywords: Tuberculosis Rifamycins RNA polymerase Mycobacteria Review

With nearly one-third of the global population infected by Mycobacterium tuberculosis, TB is still a major infectious cause of death. Indeed, in 2006 over nine million new cases and 1.7 million deaths occurred due to TB.1 The problem is particularly severe in parts of Asia and Africa where TB is often present in AIDS patients. Due to the success of the “directly observed therapy short course” (DOTS) of a standard cocktail of medicines, the situation in the United States is much better. However, this approach has been more difficult to implement in the developing world, a condition which is exacerbated by the long treatment times (six to nine months) and the numerous side effects and drugedrug interactions that result from the combination of agents required to minimize the development of resistance. Thus, even in the developed world there is significant concern about the multi-drug-resistant (MDR) strains of TB that have arisen with an estimate in 2006 of 0.5 million MDR-TB cases worldwide.1 Despite these appalling statistics, there have been relatively few new agents discovered in the past 40 years to treat TB. The rifamycins, * Corresponding author. Tel.: þ1 734 764 2202; fax: þ1 734 647 8430 E-mail address: [email protected] (G.A. Garcia). 1472-9792/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tube.2010.02.001

long considered a mainstay of TB treatment were a tremendous breakthrough when they were developed in the 1960's, particularly when rifampin (rifampicin, rifadinÒ, Figure 1) was shown in combination therapy to reduce the overall TB treatment time from 18 to 9 months.2,3 One particularly attractive feature of the rifamycins is their sterilizing activity, a property possessed by relatively few anti-TB drugs.4 Currently there are four rifamycins approved in the U.S. (Figure 1); however, rifabutin (mycobutin, LM 427, Figure 1),5e7 though it shows clinical activity against TB, was actually approved in 1992 for the treatment of Mycobacterium avium complex (MAC) in AIDS patients. Rifaximin8,9 (originally called L/105, Figure 1), which is not orally absorbed, was approved in 2004 but is only indicated for the treatment of traveler's diarrhea caused by enteropathogenic Escherichia coli. Rifapentine (initially called DL 473, Figure 1) is a long-acting version of rifampin, which was approved in 1998 for the twice weekly treatment of TB versus the once daily regimen generally utilized with rifampin.10e13 There have also been several earlier rifamycins that were developed to treat TB and some other infections, notably rifamycin SV14 and rifamide15 (Figure 2); however, these early compounds had

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Figure 1. Structures of rifamycins marketed in the United States (typical rifamycin numbering system is shown with rifampin).

poor pharmacokinetic (PK) properties and so were quickly replaced with rifampin which had much improved ADME attributes. Most recently, an interesting new analog, rifalazil (KRM-1648, ABI-1648, Figure 2) was investigated.16,17 This compound had a number of advantages over rifampin; unfortunately, its development was halted because of major side effects seen in the clinic.5,12 While the rifamycins display many admirable qualities, they still have a number of shortfalls. Especially problematic is the rapid selection of resistant mutants, particularly when used in monotherapy. Even in combination chemotherapy, a six-to-nine month treatment regimen is typically utilized to eradicate TB during which the development of drug resistance is enhanced due to poor patient compliance with treatment. Although rifampin and other rifamycins are generally well tolerated, there are some problematic side effects, including hepatotoxicity and, especially at higher doses or with intermittent dosing of rifampin, a flu-like syndrome. Finally, rifampin is a potent cytochrome P450 (CYP) inducer and inhibitor of hepatic transporters, resulting in numerous drugedrug interactions that complicate therapy, particularly in AIDS patients. New agents are needed that will: 1) shorten the duration of treatment, ideally to three months or less; 2) be more effective against MDR-TB; and 3) be more effective in the treatment of latent TB (the latent form of TB is particularly difficult to eradicate). Most impactful would be well-tolerated agents that would shorten the duration of treatment or allow more intermittent therapy.12 Given the challenges of the current issues with rifamycinderived drugs, and the more than 40 years of analog investigation, why consider additional investment in the search for improved analogs? Certainly, the mechanism of action is a proven one and rifampin is a key component of most anti-TB regimens. As will be

described in some detail in comments that follow, analog work to date has already shown that the PK properties of rifampin can be improved (e.g., with rifapentine and rifalazil), that drugedrug interactions can be at least partially ameliorated (as with rifabutin and rifalazil), that the various rifamycins have somewhat differing toxicities, and that some progress can be made against resistant TB strains (e.g., with rifalazil as well as some new analogs prepared by a Spanish group). Indeed, some recent advances in the understanding of the PK/PD relationships suggest that the duration of treatment with rifamycins can be shortened, particularly if higher doses can be tolerated. Also, a key enabling technology not available until the last few years is the availability of crystal structures of rifamycins bound to their biological target, and this important advance examined in the next section suggests ways for improving potency, including against resistant strains. It should be recognized that receiving market approval for a new rifamycin analog will not be easy and the clinical trials will be expensive. To be approved as a first line agent will require large numbers of patients and multiple months of therapy because it will be necessary to compare the new rifamycin head-to-head with rifampin in the typical combination chemotherapy protocol in the registration trials. Even to show non-inferiority will be challenging because rifampin itself is so effective in combination in this population. While it might be easier to show effectiveness in patients who have failed the initial course of therapy due to resistance to rifampin, this will likely be a much sicker population and will clearly then require a new rifamycin analog that is not cross-resistant with rifampin. This review describes important aspects of the rifamycins, starting with a description of their mechanism of action, followed by the specifics of their SAR, an overview of their PK/PD relationships, ADME

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Figure 2. Additional rifamycins of historical interest.

attributes, drugedrug interactions, and toxicities. We should note a number of other recent reviews that are pertinent to this subject. Rothstein et al. published an expert opinion on the development potential of benzoxazinorifamycins (including rifalazil)16 and a follow-up report in 2007 on their use in the treatment of Chlamydia-based persistent infections.17 In 2006, Tomioka discussed the then-current status of antituberculous agents with special reference to their in vitro and in vivo antimicrobial activities.7 Researchers at the Global Alliance for TB Drug Development authored a chapter, “Antimycobacterial Agents”, in Comprehensive Medicinal Chemistry II, in which they concluded that the “lengthy and complex treatment regimens, lessening rates of patient adherence” have “created a significant drug resistance problem and hampered control of the global TB epidemic”.18 In 2007, Portero and Rubio reviewed a number of new anti-tuberculosis therapies including quinolones, nitroimidazoles, oxazolidinones, but only very briefly mentioned rifamycins.3 In the same year, Protopopova and colleagues at Sequella Inc. summarized five new drugs that had entered clinical trials in the preceding 4 years.19 In a 2008 issue of Drug Discovery Today, Rivers and Mancera briefly reviewed new anti-MTB drugs in clinical trials focusing on those with novel mechanisms of action (e.g., nitroimidazoles).20 Other reviews have stressed the obstacles to global control of tuberculosis.21e23 Most pertinent to this review, are the recent discussions by Chopra24 and by Mariani and Maffioli25 of newer agents directed against bacterial RNA polymerase. 1. Mechanism of action The rifamycins were first isolated by scientists at Lepetit SA as a mixture of natural products, with rifamycin B (Figure 2) being the first compound identified.26 The rifamycins are members of the

ansamycin family of antibiotics, consisting of an ansa poly-hydroxylated bridge connecting two ends of a naphthoquinone (or naphthohydroquinone) core, and are structurally related to tolypomycin Y and the streptovaricins (Figure 3).27,28 They display activity against Gram-positive bacteria and to a lesser extent Gram-negative bacteria. Particularly important is their activity against mycobacteria. Early studies showed that they had a unique mechanism of action, exhibiting specific inhibition of DNA-dependent RNA synthesis in prokaryotes.29e34 Binding constants for prokaryotic RNA polymerases (RNAP) are in the range of 108 M whereas those for eukaryotic enzymes are at least 10,000 fold weaker. The initial biochemical studies were strongly supported by resistance studies where single point mutations in the bacterial RNA polymerase enzyme account for the vast majority of rifamycin resistance.35e37 Later studies indicated rifampin totally blocked the translocation step that would normally follow formation of the first phosphodiester bond by the polymerase, suggesting that rifamycins sterically block the extension of the RNA chain at this very early stage.38 The DNA-dependent RNA polymerase is a complicated enzyme with an a2 b b0 s-subunit structure. The binding site for the rifamycins on RNA polymerase has been shown to be at the b-subunit encoded by the rpoB gene. A key breakthrough has been the determination of the crystal structures of several different inhibitors with the RNA polymerase (recently reviewed by Ho et al).39 The initial study was done with rifampin and showed the compound binding in A the b-subunit deep within the DNA/RNA channel but more than 12  from the Mg2þ ion at the active site of the enzyme.40 The polymerase has key hydrogen bond interactions with the four hydroxyl groups (at C-1, C-8, C-21, and C-23) of rifampin, consistent with the known SAR (vide infra) of the rifamycins, as well as the carbonyl oxygen of the C-25 acetoxy group (Figure 4). Additional hydrophobic

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Figure 3. Some related members of the ansamycin class of antibiotics.

interactions were noted as well, and this structure helped explain the high resistance that results from single point mutations since these alter the amino acids found to have direct interactions with the backbone of rifampin. This study also suggested that rifampin obstructs the growing oligonucleotide chain after the first or second chain elongation step. This finding was consistent with earlier biochemical experiments which showed that rifamycins do not prevent the initiation or translocation steps, nor is the polymerase enzyme sensitive to rifamycins after it carries a longer RNA chain.40 Another investigator used FRET measurements to propose a model of rifampin and rifamycin SV binding to the RNA polymerase of E. coli; however, while the agreement to the 3.3  A crystal structure of the Thermus aquaticus RNAP was quite good, the FRET approach produces a much lower resolution structure.41 While the initial crystal structure and steric block model (Figure 5) was an important step forward and was consistent with most of the earlier biochemical and resistance studies, there were some results that were not readily explained by this model. For example, it has been shown that some rifamycins, e.g., rifalazil, are not completely cross-resistant to rifampin, and that rifabutin and rifalazil can develop a different subset of resistant mutations than does rifampin.42 Recognizing this, Artsimovitch and colleagues, in their 2.5  A structural biology studies with rifapentine and rifabutin bound to the RNA polymerase from Thermus thermophilus, proposed a more advanced model involving allosteric modulation of the RNA polymerase catalytic reaction as a key element.43,44 Their primary insight was to recognize that rifamycins, such as rifampin and rifapentine with a C-3 tail only, form a different subclass relative to rifamycins such as rifabutin and rifalazil, where there is a C-3/C-4 tail occupying a different chemical space in the enzyme pocket. The classical rifamycins such as rifampin and rifapentine were proposed to work via the b-subunit where interactions with the ansa side chain generate an allosteric signal to the active site so as to inhibit the second phosphodiester bond formation. On the other hand, the newer rifamycins such as rifabutin and rifalazil have additional contacts via their C-3/C-4 tail with the s-subunit, which was proposed to inhibit the formation of the first phosphodiester bond via a different allosteric pathway. Both pathways reduce affinity for the catalytic Mg2þ ion (magenta color in Figure 5) and cause dissociation of the Mg2 and short, unstably bound RNAs (yellow in Figure 5) from the initiation complex.43 Recently, this allosteric modulation model proposed by Artsimovitch and colleagues has been challenged.45 Artsimovitch et al. had made four assertions in support of their allosteric mechanism: 1) rifamycins decrease the affinity of Mg2þ to the RNAP active site, 2) high Mg2þ concentrations confer resistance to rifamycins, 3) two of the most significant rifamycin-resistant mutations, b-D516N and

b-D516V, do not affect the affinity of rifamycins for RNAP, and 4) a designed mutation based on the allosteric model, b-L1235A, confers resistance to rifamycins but does not decrease the affinity of the rifamycin to RNAP.43 Feklistov et al. revisited each of these assertions and found a number of concerns with the design of the experiments that supported them.45 More careful studies directly measuring Mg2þ binding showed no change in Mg2þ affinity in response to rifamycins and that higher concentrations of Mg2þ did not confer resistance to rifamycins.45 Further, they found that the IC50 and KD of rifampin for the D516 mutants were dramatically increased, consistent with resistance due to decreased affinity and they found no evidence for an allosteric mechanism.45 Finally, they examined the designed mutation, b-L1235A, and found only a very modest (ca. 2-fold) increase in resistance to rifampin that correlates with rifampin binding.45 The conclusion of these very careful studies is that the rifamycins inhibit RNAP via the steric occlusion model by blocking the exit of the growing RNA chain (Figure 5). This has fortunate implications for TB drug development. The steric occlusion model suggests that inhibitors with additional binding interactions (increasing their free energy of binding) will be able to overcome resistant mutations as these mutations only reduce the binding affinity of the inhibitors for RNAP. In fact, it may be possible to develop inhibitors that bind tighter to a resistant mutant than to wild-type RNAP. This structural model should be a useful aid in the design of novel agents to better interact with the s-subunit and lead to the preparation of analogs with improved potency, including against MDR strains. Utilizing new ribosome interactions to overcome resistance has proven successful in the past with other compound classes of protein synthesis inhibitors, such as the discovery of the ketolides to overcome the typical mode of macrolide resistance. In addition, scientists are already doing homology modeling with the RNA polymerase of M. tuberculosis, both wild-type and mutant strains, in an attempt to design improved analogs; one suggestion was that adding electron donating groups at C-14, C-28, C-34, and C-37, or an electron accepting group at C-13 and/or C-18 of the rifamycins could enhance the inherent affinity for the RNA polymerase.46 Given the attractiveness of this biological target for TB treatment, investigators are also looking for completely novel classes of RNA polymerase inhibitors.24,25,47e49 Finally, it should be mentioned that although for M. tuberculosis all the rifamycin-resistant strains characterized to date appear to have mutations in the RNA polymerase, this is not the case with other mycobacteria. Indeed, in M. smegmatis, ADP-ribosylation of the C-23 alcohol via a rifampin ADP-ribosyltransferase enzyme generates high level resistance to rifamycins.50 Should plasmid transfer to M. tuberculosis take place in the future, the recently

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Figure 4. Interaction of rifampin with amino acids of Thermus aquaticus DNA-dependent RNA polymerase in the antibiotic-enzyme complex. The amino acid numbering is for Thermus aquaticus rpoB. Amino acids forming van der Waals and hydrogen-bonding interactions are indicated. The side chains of the hydrogen-bonding amino acids explicit, with their carbon atoms in black. The carbon atoms of the rifampin are orange. Reproduced with permission from: Campbell EA, Korzheva N, Mustaev A, Murakami K, Nair S, Goldfarb A, Darst SA. Structural mechanism for rifampicin inhibition of bacterial RNA polymerase. Cell 2001; 104:901e12. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Figure 5. The steric block model for the mechanism of action of rifamycins. The drawing illustrates the binding of rifampin (ansa backbone in black and C-3 tail in turquoise) sterically blocking the growing RNA chain (yellow) in the transcription initiation complex of RNAP (gray), sigma factor (magenta), and DNA template (red) and non-template (blue) strands. Some distance from the rifamycin-binding pocket is seen the Mg2þ ion (magenta ball) at the catalytic site. Reproduced with permission from: Artsimovitch I, Vassylyev DG. Is it easy to stop RNA polymerase? Cell Cycle 2006; 5:399e404. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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published 1.45  A co-crystal structure of rifampin bound to the ADPribosyltransferase should prove useful in the design of agents less prone to this mode of resistance.51 2. Structureeactivity relationships The anti-TB activity of the rifamycins is generally directly related to their potency at the DNA-directed RNA polymerase enzyme; however, lack of activity in cell culture can also be due to the failure of the rifamycin to penetrate the cell envelope. While most of the reported SAR for rifamycins is in cell culture, there have been some studies with the RNA polymerase and this SAR will be discussed first. It should also be mentioned that there have been some attempts to optimize the reverse transcriptase and mammalian RNA polymerase inhibitory activities of the rifamycins so as to treat viral infections or cancer; however, these activities are much weaker than the bacterial RNA polymerase inhibitory activity.52e56 Not much success has occurred with these antiviral and anticancer efforts, and they will not be discussed here other than to mention that typically the best activity was seen with highly lipophilic side chains at C-3 (often leading to non-specific inhibition in the micromolar range). The rifamycins are the most potent inhibitors of DNA-dependent RNA polymerase known with an EC50 for rifampin against the E. coli polymerase of about 20e30 nM.31,57 Initial studies indicated that most modifications of the ansa bridge led to less active compounds. For example, acetylation of either the C-21 or C-23 alcohol, or hydrogenation of any of the double bonds in the side chain had a deleterious effect on activity at the enzyme level. For example, the 16,17,18,19- tetrahydro analog of rifamycin SV was at least 3-fold less active than the parent, and the 16,17,18,19,28,29-hexahydro analog reduced activity by three- to ten-fold relative to rifamycin SV (Figure 2). The C-21, C-23-diacetylated analog was nearly completely inactive.57 Similarly, rifamycin YS, an analog of rifamycin SV, which has a keto group instead of a hydroxyl at C-21 as well as an additional hydroxyl group at C-20, was completely inactive in the RNA polymerase assay. The epoxy side chain derivatives (e.g., 18,19-epoxy rifamycin S) had only weak activity at best.58 Although tolypomycin and streptovaricin C (Figure 3) have some RNA polymerase activity, they are considerably weaker inhibitors than rifamycin SV, having about 10% the potency of rifampin.33,59,60 Ring-opened rifamycin analogs typically were inactive.58 Rifamycin W (Figure 6) which still maintained an ansa bridge was essentially inactive; however, in contrast, damavaricin C (Figure 6), the hydrolysis and hydroquinoneoxidation product of streptovaricin C, had roughly equivalent inhibitory activity against RNA polymerase as streptovaricin C (though it lacked any antibacterial activity).28,61,62 One important modification of the side chain that was well tolerated was the C-25 hydroxylated

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analog (formed by hydrolysis of the C-25 acetyl group) of rifamycin SV; this compound had equivalent potency as rifamycin SV.58 Modifications of the naphthalene ring were better tolerated, with the significant exception that acetylation of the C-8 hydroxyl group eliminated activity.58 An important early SAR point was that rifamycin S (Figure 7, the quinone oxidation product of the hydroquinone rifamycin SV) is equiactive with rifamycin SV. Similarly, rifamycin B and rifamide (Figure 2) were almost as active as rifamycin SV.34,57 Rifamycinol (the C-11 alcohol resulting from the reduction of the C-11 ketone group in rifamycin S) was also roughly equivalent in potency to rifamycin S.34,63 A wide variety of substitutions at C-3 in rifamycin S or rifamycin SV (where there is a hydrogen atom at C-3) are tolerated. For example, the C-3 morpholino group is nearly as potent against the RNA polymerase as rifamycin SV.58 Similarly, the C-3 carbomethoxy congener, though inactive in cell culture (presumably a penetration issue), is essentially as active as the parent.64,65 A study by Whitlock of a variety of simple substituents at C-3, all of which were active, led to the conclusion that electronegative groups (such as found in rifampin) enhance activity, with 3-halo rifamycin SV derivatives being somewhat more potent against the enzyme than rifampin and 3-amino groups a bit less active.66,67 He proposed that the naphthoquinone core was involved in a donoreacceptor p-complex with the enzyme, such as with a tyrosine in the polymerase. Subsequent crystal structure studies with the various C-3 substituted analogs also suggested that the electronegativity of the C-3 group influenced the orientation of the C-15 amide carbonyl.68,69 Indeed, much of the early work (in the absence of a co-crystal structure with the polymerase) utilized crystal structures to show that the active conformation of the ansa bridge was maintained in potent compounds (presumably to properly present the C-21 and C-23 alcohols to the polymerase) whereas in the less active analogs, the conformation was distorted.64,65,70e72 One anomaly was the crystal work done with rifamycin O (Figure 7, an oxidation product of rifamycin B), a compound with essentially equiactive potency at the RNA polymerase to rifamycin SV but with an altered ansa side chain conformation in the crystal state.73,74 One explanation was that the acetal ring is cleaved in the enzyme assay permitting the ansa side chain to achieve the appropriate conformation. The SAR of some early rigid analogs was also revealing. Interestingly, the RNA polymerase inhibitory activity of the benzannulated analog 1 (rifazine, Figure 8 e note similarity to the structure of rifalazil) was nearly equal to that of rifamycin SV.34,58 On the other hand, the rigidified amide analog 2 (Figure 8) was essentially inactive.58 It should be noted that most of these studies utilized the RNA polymerase from E. coli rather than polymerases from mycobacteria (an exception is the many studies done with the clinical candidates

Figure 6. Structures of rifamycin W and damavaricin C.

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against resistant strains of tuberculosis). One study did compare the inhibition by rifampin and rifalazil of the RNA polymerase from M. avium.75 In this study, whereas the two compounds were equiactive against the E. coli polymerase, rifampin was about three-fold more potent than rifalazil against the M. avium enzyme. Additionally, the potencies against E. coli and M. avium polymerases were all in the 70e200 ng/mL range. In contrast, several studies with rifampin have shown that it is 1000 times more potent against M. tuberculosis RNA polymerase than E. coli RNA polymerase.76,77 Initially this was thought to result from differences in the constitution of the portion of the b-subunit that interacts with rifampin.76 However, this portion of the polymerase is highly conserved between the two species, and when the b-subunit in E. coli was replaced with that from M. tuberculosis in the E. coli polymerase, the inhibitory activity of rifampin against the chimeric polymerase did not improve.77 Thus, other structural features in the E. coli polymerase (perhaps in the s-subunit?) were responsible for the difference. The structureeactivity relationships of the rifamycins against the E. coli RNA polymerase agree quite well with the results of the rifamycin-RNAP co-crystal structures (note that rifampin is 100-fold less active against the T. aquaticus polymerase than against the E. coli polymerase).40,77 However, the SAR against bacteria are somewhat more complicated because certain analogs are unable to significantly penetrate into the bacteria. While analogs that had poor RNA polymerase activity did not show significant antibacterial activity, having potent RNA polymerase inhibitory activity did not guarantee antibacterial activity. For example, while the RNA polymerase inhibitory

activities of rifampin against both Gram-positive and Gram-negative bacterial polymerases were quite similar, rifampin is much more potent against Gram-positive bacteria because of the well known problem of penetration through the cell walls in Gram-negative organisms.2 Furthermore, as noted above, analogs such as 3-carbomethoxy-rifamycin SV (presumably because of hydrolysis to the carboxylic acid which does not penetrate the cell) and even rifamycin B, the original rifamycin identified, have good polymerase activity but do not show a significant antibacterial effect in cell culture.64,78 Nevertheless, a good bit of useful SAR information can be gleaned from studies against Gram-positive bacteria in general and M. tuberculosis in particular (when available). Much of the early work again was done by the Italian group at Lepetit along with scientists at Ciba-Geigy with whom they had formed a collaboration on rifamycins.28,78,79 As with inhibition of RNA polymerase, the best activity against Gram-positive bacteria and mycobacteria required: 1) free hydroxyl or keto groups at C-1 and C-8; 2) unbroken ansa bridge; and 3) free hydroxyl groups at C-21 and C-23.28,78 Changes to the ansa bridge which disrupted the conformation present in rifamycin SV typically led to loss of activity with the rifamycin analog. However, the slight conformational change seen in rifamycinol (the C-11 alcohol reduction product of rifamycin S) that results in some increased flexibility in the ansa chain was not deleterious to activity since in both Staphylococcus aureus and E. coli rifamycinol was equivalent in potency to rifamycin S.63,78 The streptovaricins had somewhat different structural activity relationships than the rifamycins.28 Indeed, streptovaricin J (with

Figure 8. Structures of some early rigidified rifamycin analogs.

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an acetate at C-21) was still active.28 At one time, the streptovaricins, and particularly streptovaricin C (Figure 3), were of interest because of their activity against TB; however, even though their potency was reasonable, it was still not as impressive as the rifamycins which soon became the ansa class of higher interest against TB.80 Damavaricin C (Figure 6), though similar in potency against the RNA polymerase enzyme, was a considerably weaker antibacterial than streptovaricin C; however, long chain ethers at the C-19 phenol of damavaricin led to several analogs significantly more potent than streptovaricin C against M. stegmatis.62 Tolypomycin Y (Figure 3) and C-3 substituted analogs of tolypomycinone (a degradation product from the hydrolysis of the C-5 imine of tolypomycin Y) were about three- to four-fold less potent than rifampin against M. tuberculosis in cell culture.81,82 Initially, rifamycin SV (Figure 2) was of high interest because of its very potent activity against Gram-positive bacteria in cell culture, especially M. tuberculosis.14,79 However, it was poorly absorbed from the GI tract and is not typically used against TB, though it is on the market (first introduced in 1963) in several countries as the sodium salt for the parenteral or topical treatment of some other infections.79 While rifamycin B (Figure 2) was inactive in cell culture because of the inability of analogs with the free carboxylic acid to penetrate the bacterial cell wall, the corresponding amides and hydrazides had much improved activity.83 These amides and hydrazides, especially when disubstituted, had excellent activity in vitro against TB as well as activity in mouse models.83 Among this class, the diethylamide rifamycin B derivative (rifamide, Figure 2), with potency against TB similar to rifamycin SV, had the best therapeutic index and was introduced into clinical practice in 1965.15,79,84 However, rifamide was also found to suffer from PK liabilities and found only sparing use after the introduction of rifampin into the marketplace. Much of the subsequent successful SAR then concentrated on substitutions at the C-3 position of the rifamycins, in part because such a wide variety of substituents were well tolerated and highly active analogs were produced. Numerous substituents, including 3-amino, 3-imino, 3-aminoalkyl, 3-alkylamino, 3-thioalkyl and 3-hydrazido, were investigated, and many active analogs were found.82,84,85 For example, the C-3 amino derivative was several fold more potent than rifamycin SV.86 It was also noted that any of the C-3 side chains ending in a carboxylic acid tended to reduce or eliminate activity in cell culture, presumably by reducing cellular penetration.87 However, the key breakthrough was with the preparation of imines, hydrazones, and oximes via the readily available 3-formylrifamiycin SV, itself a degradation product of the rather unstable 3-dialkylaminomethyl rifamycin derivatives.79 Out of this initial effort of several hundred analogs came rifampin, discovered in 1965 and introduced into clinical practice in 1968.2,79 Rifampin not only has superb activity against M. tuberculosis, being equipotent in cell culture with rifamycin SV, but it also has the PK properties that allow for once a day oral dosing.14 Thus, rifampin has been a mainstay in TB therapy for decades. Much subsequent effort focused on improved analogs of rifampin, particularly compounds with a longer half-life so as to hopefully permit intermittent dosing. Indeed, numerous rifampin analogs have been prepared and tested with particular emphasis on hydrazones at C-3. Among the many hydrazone analogs evaluated, rifapentine, a simple rifampin analog with the terminal methyl group on the C-3 side chain replaced with a cyclopentyl group and, like rifampin, originally prepared at the LePetit Labs, stood out.10,13,88 It was two to ten times as potent as rifampin in cell culture against M. tuberculosis, although it was still completely cross-resistant with rifampin.88,89 In addition, rifapentine had a significantly longer half-life than rifampin and is effective in TB patients with twice weekly dosing.10,13

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Other C-3 substituted rifampin analogs also had interesting activity. Quite a few active oximes were reported; for example, reaction of 3-formylrifamycin SV with methylhydroxylamine produced an oxime that was five to ten times as potent as rifampin in cell culture against M. tuberculosis.90 Researchers at Farmitalia Carlo Erba published a series of azinomethylrifamycins (Figure 9, structure 3 where R1 ¼ H and R2 is a secondary amine).91,92 Among the most potent compounds in this new series against TB was the piperidine analog FCE 22250 which had equivalent potency to rifampin in cell culture.91 FCE 22250 was also of interest due to its long half-life in plasma (about three times that of rifampin).91 During these studies the Carlo Erba group also noticed a rearrangement in which the hydrazine precursor to compounds like FCE 22250 attacked the C-15 amide carbonyl to generate the C-2 aniline and now a ring expanded ansa side chain.93 Not surprisingly, these ansa bridge altered compounds were inactive.93 Rifametane (4, Figure 9) was another azinomethyl rifamycin of interest because of its excellent activity and improved half-life relative to rifampin. Rifametane (also known as SPA-S-565 and CPG40/ 469A) was initially reported to be comparable in potency to rifampin against M. tuberculosis in cell culture.94 A later study indicated that 4 was equipotent in terms of MICs against M. tuberculosis in comparison to the quinone form of FCE 22250 (recall the interconversion of rifamycin SV and rifamycin S) and four-fold more potent than rifampin; however, in terms of bactericidal activity it was less potent than rifampin which was less potent than FCE 22250.95 More recently a group in Bulgaria reported some analogs closer in structure to rifampin, in particular the cinnamyl-rifampin analog T9 (5, Figure 9, trans form shown) which was initially reported as being four to ten times as potent as rifampin in cell culture against M. tuberculosis, including several drug-resistant strains.96 In a subsequent study comparing T9 to rifampin, rifabutin, and rifalazil (Figure 2), T9 was only slightly more potent than rifampin and considerably less potent than rifabutin and rifalazil.97 There has also been a very recent report of 2-piperidyl analogs attached to the C-3 position of rifamycin SV (e.g., compound 6 in Figure 10).98 While some activity against TB in cell culture was reported, these compounds did not appear to be as potent as rifampin. In the patent literature, there have been quite a few additional 3-substituted rifamycin analogs prepared, although biological details are scarce. For example, in the older literature 3-nitrorifamycin SV has been prepared,99 as have 3-sulfonyl analogs,100,101 and 3-piperazino analogs.102,103 More recently, 3-azido rifamycin analogs,104 3-carbamate analogs,105 3-amino-oxyethyl derivatives,106 and the unusual heterocyclic analog 7 (Figure 10), which harkens back to the azino analogs in Figure 9, have been reported in the patent literature.107 Finally, it should be mentioned that there have been several QSAR papers attempting to explain the antibacterial activity of various rifamycins. Early QSAR efforts to model the TB activity with the rifamide analogs and the C-3 methylhydrazones were not very informative.108,109 More recently, there have been additional attempts to model the antimycobacterial activity of the 3-substituted analogs (mainly the hydrazones).110,111 A large number of rifamycin analogs containing an additional ring via linking of the C-3 and C-4 positions have been prepared over the years and several have made it to the market for various indications. One such compound is rifaximin (Figure 1) which was about half as potent as rifampin at inhibiting Staphylococcus epidermidis DNA-dependent RNA polymerase and similar in potency to rifampin in cell culture.112 However, rifaximin is not orally absorbed, in part because of its inclination to exist in a zwitterionic form (with a positive charge on the nitrogen at C-3 and a negative charge on the nitrogen at C-4, shown in Figure 1) and to self associate, and thus its only approved indication is for traveler's diarrhea.8,113

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Figure 9. Structures of C-3 substituted rifamycin analogs (rifampin analogs).

More simplified C-3/C-4 five-membered ring heterocyclic analogs are shown in Figure 11. Thiazole 8 derivatives wherein R1 was methyl and R2 was ethyl or n-butyl were about twice as potent as rifampin against M. tuberculosis.114 When NR1R2 was piperidine or N-methylpiperazine, potency was equivalent to or one-quarter that of rifampin, respectively.114 When 3-aminorifamycin S was derivatized to produce the related five-membered ring fused product, namely imidazole 9 (Figure 11), excellent activity in vitro against M. tuberculosis was again achieved with either alkyl or amino substituted analogs.86,115 For example, when R ¼ cyclohexyl in compound 9, potency twice that of rifampin was reported.86 When R was either hydrogen or straight chain alkyl, comparable potency relative to rifampin was seen. Similarly, amino substituted analogs of 9 were generally comparable in potency to rifampin, including compound 9 with R as a piperidine or N-methylpiperzine group.115 A key discovery was the synthesis of the related spiro-piperidylrifamycin analogs 10 (Figure 12), where the original series (R2 ¼ R3 ¼ H) was also readily prepared by Farmitalia Carlo Erba researchers from 3-aminorifamycin S.86,116 Among the earliest reported compounds, the N-methyl (R1 ¼ Me, R2 ¼ R3 ¼ H) and N-isopropyl (R1 ¼ i-Pr, R2 ¼ R3 ¼ H) derivative of 10 were noted as being comparably active in cell culture as rifampin against M. tuberculosis whereas the longer chain amines (e.g., R1 ¼ n-butyl to n-heptyl) were four-fold more potent than rifampin.86,116 Particularly noteworthy was rifabutin (Figure 1) which was even more active, initially reported as being about ten-fold more potent than rifampin and several fold more potent than FCE 22807 (the quinone version of FCE 22250 in Figure 9).116,117 In a series of tests, rifabutin has subsequently been found usually to be about four to eight-fold more potent than rifampin (and is at least as potent as rifapentine).7 While the majority of rifampin-resistant strains are still cross-resistant to

Me

Me

HO Me AcO OH O HO OH Me Me Me NH MeO

rifabutin, there are still significant numbers of rifampin-resistant strains that are sensitive to rifabutin.6,118,119 While rifabutin has shown activity in the clinic for the treatment of TB, in the U.S. it is actually approved for the treatment of M. avium, where it is somewhat more effective than rifampin.6,120 An exciting new development in rifabutin analogs comes from Spain where rifabutin congeners substituted on the piperidine ring (e.g., compound 10 in Figure 12 where R1 ¼ R3 ¼ H and R2 ¼ phenyl) show improved activity relative to rifampin and rifabutin against rifampin-resistant and rifabutin-resistant strains.121 For example, compound 10, as well as its isomer where the stereochemistry at the two R2 groups is inverted, shows potency comparable to rifabutin against drug-sensitive strains of M. tuberculosis; however, against the rifampin and rifabutin-resistant strains, the same compound is at least ten-fold more potent as rifabutin against the resistant strains, exhibiting submicromolar MICs (the isomer where the stereochemistry at the two R2 groups is inverted is not active against the resistant strains).121 The assignment of stereochemistry to these substituted piperidines has been described,122,123 and additional analogs also containing an R3 substituent (see Figure 12) have been reported in the patent literature by the Spanish group.124 It would certainly be of value to obtain co-crystal structures of these analogs with the RNA polymerase to determine whether there are additional interactions with the polymerase. Several interesting homologated rifabutin analogs have also been published by Cumbre researchers.125 These spirorifamycin analogs (compound 11 in Figure 12 where n is 1 or 2) were reported as being within two to four-fold dilutions of rifabutin in potency; for example compound 11 where n ¼ 2 and R ¼ i-butyl was half as potent as rifabutin against a S. aureus strain. Against a strain of S. aureus made resistant to rifabutin by virtue of an rpoB mutation,

Me Me HO Me AcO OH O HO OH Me Me Me NH MeO

O O

O O Me

O

OH HN Me

Me

O O

OH

Me 7

6 Figure 10. Recent C-3 substituted rifamycin analogs.

N

N

Me N S

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Me

Me Me HO Me AcO OH O HO OH Me Me Me NH MeO

Me

HO Me AcO OH O HO OH Me Me Me NH MeO

O

S

O O

N

O

NH

O O

NR1R2

Me

103

N

R

Me 9

8 Figure 11. C-3/C-4 fused heterocyclic rifamycin analogs.

several of the homologated analogs (e.g., 11 where n ¼ 2 and R ¼ methyl) were clearly more potent than rifabutin.125 Considerable progress has also been made with rifamycin analogs wherein the C-3 and C-4 substituents are linked to form a sixmembered aromatic ring. The earliest reported example of this is rifazine (compound 1, Figure 8; also compound 12, Figure 13, wherein R1 ¼ R2 ¼ H).86,126 The initial report indicated activity against M. tuberculosis of the same magnitude as rifamycin SV (Figure 2)126; however, subsequently more detailed data showed the potency of rifazine in cell culture to be one-tenth that of rifamycin SV and equivalent to 4-deoxyrifamycin SV.127 On the other hand, rifazine and its derivatives are considerably more potent against S. aureus than rifamycin SV.128,129 For example, rifazine and its methyl derivative 12 (R1 ¼ H and R2 ¼ Me) are about ten-fold more potent than rifamycin SV against one strain of S. aureus.128 Ciba-Geigy researchers also reported on the corresponding phenoxazine analogs of rifazine (13, Figure 13).128,129 While the data were limited, the compounds appeared to have similar activity against M. tuberculosis; however, the phenoxazine analogs had slightly reduced potency against S. aureus. For example, the directly corresponding oxygen analog of rifazine (13, R1 ¼ R2 ¼ H) and the methyl analog (13, R1 ¼ H and R2 ¼ Me) were respectively three-fold and five-fold more potent than rifamycin SV against the same strain of S. aureus as indicated above for rifazine and its methyl analog.128 Scientists at Kaneka Corporation effectively exploited the chemistry of the phenoxazine core 13 to come up with a series of interesting analogs, including ultimately rifalazil (Figure 2). Initially they found that adding simple amines to compound 13 when R1 ¼ R2 ¼ H gave potent amino substituted versions of 13 wherein R1 ¼ H and

Me

HO Me AcO

HO Me

Me MeO

O

R2 ¼ NR3R4.130 For example, the dimethylamino and diethylamino derivatives were equivalent in potency in vitro to rifabutin versus M. tuberculosis. The piperidine derivative (13 wherein R1 ¼ H and R2 ¼ piperidino) was twice as potent as rifabutin.130 Even more impressive were benzoxazinorifamycin analogs 14 and 15 (Figure 14) prepared by the same Japanese group using similar chemistry.131 In terms of activity against M. tuberculosis in cell culture, the dimethylamino analog (compound 14 wherein R1 ¼ R2 ¼ Me) was four-fold more potent than rifabutin. Larger amino groups were also well tolerated.131 For example, compound 14 wherein R1 ¼ Me and R2 ¼ i-Bu was also four-fold more potent than rifabutin, and the even larger amine 14 wherein R1 ¼ R2 ¼ CH2CH2OMe was eight-fold more potent than rifabutin. In contrast, compound 14 wherein R1 ¼ Me and R2 ¼ CH2CH22-Py was only twice as potent as rifabutin. Cyclic amines were also active, with the azetidinyl, pyrrolidino, piperidinyl, and morpholino analogs of 14 being, respectively, four-fold, two-fold, one-fold, and four-fold higher in potency against M. tuberculosis relative to rifabutin. The piperazinyl analogs of 14, i.e., compound 15, also proved interesting with the N-methyl analog (15, R ¼ CH3) being twice as potent as rifabutin. The n-propyl, isopropyl, n-butyl and isobutyl analogs of 15 were similar in potency to the methyl analog, though the t-butyl analog 15 (R ¼ t-Bu) was two-fold more potent.131 Among these analogs, rifalazil (15 wherein R ¼ i-Bu, see also Figure 2) proved most interesting, not just because of its excellent potency but because of its relative lack of toxicity in early rodent studies.132 Among a series of close analogs comparing the isobutyl to the sec-butyl derivative, rifalazil was the most potent against rifampin susceptible strains of M. tuberculosis; however, in this study rifalazil was two to four-fold less potent than the n-propyl

Me

OH O O

Me

HO Me

Me MeO

NH 3 NH R

O O

N

Me

N R2

Me

HO Me AcO

R2 R1

O

OH O O

Figure 12. Rifabutin analogs.

Me NH NH

O O Me 11

10

Me

N N R

(CH2)n

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Me

HO Me AcO

HO Me

Me MeO

O

Me

OH O OH

Me NH N

O O Me

R1

HO Me

Me MeO

O

N

Me

HO Me AcO

Me

OH O O

Me NH O

O O

N

Me

R2

R1

R2

13

12 Figure 13. Rifazine and phenoxazine analogs.

and sec-butyl derivatives of 15 against several rifampin-resistant strains.132 In general, against a number of strains, the isobutyl derivative rifalazil was twice as potent as the corresponding isopropyl derivative against M. tuberculosis, including rifampin-resistant strains.118 Rifalazil is an exceedingly potent rifamycin derivative being 16e256 times more potent than rifampin.5,7,133 It is particularly effective against many of the rifampin-resistant strains of M. tuberculosis though certainly not all.133,134 Several studies involving strains with various rpoB mutations clearly indicated which mutations identified with the rifampin, rifapentine, and rifabutin-resistant strains retained sensitivity to rifalazil.119,135 Rifalazil and its benzoxazinorifamycin analogs also showed excellent activity against other organisms with rifampin-resistant mutations, including Streptococcus pyogenes, Chlamydia trachomatis, and Chlamydia pneumoniae.136,137 Rifalazil was also very effective in in vitro combinations with a variety of other antibacterials, including linezolid, suggesting a possible advantage in the clinic with such combinations.138,139 More recently, scientists at ActivBiotics reported the synthesis of novel rifalazil analogs with a variety of novel cyclic amines representing NR1R2 in compound 14 (Figure 14).17,140,141 Although the activities reported were primarily against S. aureus and S. pyogenes, many of the compounds were significantly more potent than rifalazil, including against some rifalazil-resistant isolates.140,141 Particularly interesting were the bicyclic analog ABI-0418 and the piperidine analog ABI-0299 (both shown in Figure 15), which were four-fold more potent than rifalazil against wild-type S. aureus and

up to forty-fold more potent against some of the rifalazil-resistant S. aureus strains.141 The N-methylpiperazine analog ABI-11331 (Figure 14, compound 15 wherein R ¼ Me) was reported to have similar potency as well, as did its C-25 hydroxyl derivative ABI0043 (Figure 15).140e142 Additional novel rifalazil analogs have been described by the ActivBiotics group in a series of patent applications.143e146 Although M. tuberculosis data is limited, it is clear a number of compounds are quite potent against S. aureus, including the interesting benzthiazinorifamycin analogs such as 17 (Figure 16).143 Additional analogs described in the patent applications include analogs substituted at other positions around the benzoxazino ring. Other benzoxazinorifamycin analogs reported in the patent literature (mostly earlier from Kaneka Corporation) include 40 -tert-butyl analogs (Figure 13, compound 13 wherein R1 ¼ t-Bu and R2 ¼ H)147 as well as analogs with an additional phenyl ring annulated to the benzoxazino ring.148 The Kaneka researchers had also earlier reported on charged oxazinorifamycin analogs (18, Figure 16).149 A variety of ring annulated rifamycin analogs that partially constrain the ansa bridge have been disclosed (Figure 17). Compounds 19 and 20, originally reported by a group at Merrill Dow in their search for antiviral and anticancer rifamycins,54 were later resynthesized by a European group and examined for antimycobacterial activity.150 Not surprisingly, these compounds had greatly reduced activity. While the unsaturated analog 19 had activity several fold less than rifampin, the unsaturated derivative 20 was devoid of activity against M. tuberculosis.150 Somewhat

Figure 14. Benzoxazinorifamycin analogs.

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Figure 15. Potent rifalazil analogs.

related are the pyrimidorifamycin SV analogs, exemplified by compound 21 (Figure 17) reported in a Japanese patent.151 Researchers at Cumbre Pharmaceuticals reported the preparation of a much better tolerated modification of the rifamycin core, namely the preparation of oximes at the C-11 ketone.152 These compounds showed good activity against S. aureus. For example, the C-11 oxime of rifamycin S was four-fold more potent than rifamycin S (and half as active as rifalazil) against both wild type and rifampin-resistant S. aureus strains.152 The C-11 oxime of rifalazil showed similar potency to rifalazil itself, though it was noted that the C-11 oxime of compound 15 in Figure 14, wherein R ¼ i-Pr and the hydroxyl group on the benzoxazino ring is replaced with hydrogen, was about 10-fold more potent than rifalazil.152 There have also been a few successful modifications of the ansa bridge of the rifamycins, although the early studies showed that even acetylation of the C-21 or C-23 alcohols in rifampin resulted in almost complete loss of antibacterial activity.153 Interestingly, the acetate at C-25 can be hydrolyzed to the corresponding alcohol without serious effect. As a specific example, the C-25 metabolite of rifapentine, C-25-O-desacetylrifapentine, was within one or two dilutions of rifapentine in terms of activity in cell culture against M. tuberculosis.154 Similarly, a major metabolite of rifabutin, the C-25 hydroxyl product from acetate hydrolysis, shows similar activity as rifabutin.155 Recall also that the rifalazil analog ABI-0043 (Figure 15) had excellent potency against clinical isolates.140 However, the two other identified metabolites of rifabutin, namely rifabutin derivatives wherein the C-30 or C-31 methyl groups are hydroxylated, were much less potent in cell culture than the parent compound.155

An interesting observation was made by Ciba-Geigy researchers with the report that the C-25 malonate derivative CGP 4832 (22, Figure 18), though similar in activity in cell culture to rifampin against Gram-positive organisms, was up to 400 times more potent than rifampin against E. coli.156 This enhanced sensitivity (relative to rifampin) against some Gram-negative organisms was ultimately attributed to the efficient uptake of this compound by the TonB inner membrane protein assisted by the outer membrane protein FhuA.157,158 In a more recent development, researchers at Cumbre cleverly designed a series of C-25 carbamates (23, Figure 18) to be effective against rifampin-resistant strains of M. stegmatis.159,160 These carbamates (e.g., 23 wherein NR1R2 was 4-(benzylamino)1-piperidine) had over a hundred-fold enhanced potency relative to rifampin against some M. stegmatis strains resistant via the ADPribosylation transferase enzyme, as well as somewhat enhanced activity against some strains of E. coli.160 Cumbre researchers have also prepared novel rifamycin-quinolone hybrids that are very effective against Gram-positive organisms, in particular S. aureus.161,162 The lead compound CBR-2092 (24, Figure 19) had gatifloxacin-type activity in vitro against rifampin-resistant S. aureus and rifamycin-like potency against strains resistant to fluoroquinolones.161,162 In the patent literature the Cumbre group also reported the preparation of rifamycinnitropyrrole hybrids (Figure 12, compound 10 wherein R2 ¼ R3 ¼ H and R1 ¼ ethyl-N-(2-methyl-5-nitropyrrole))163 as well as some rifalazil-quinolone hybrids.164 In summary, numerous active analogs have been made through the years, but rifampin still remains as the cornerstone rifamycin for

Figure 16. Analogs reported in the patent literature.

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Figure 17. Ring annulated rifamycin analogs that constrain the ansa bridge.

the treatment of TB. However, the piperidine ring substituted rifabutin analogs prepared by Barluenga et al.121 (10, Figure 12) and the new rifalazil analogs prepared by the ActivBiotics researchers (Figure 15)140,141 represent promising leads, especially when activity against a variety of rifampin-resistant clinical isolates of TB is observed. It would also be of great value to obtain co-crystal structures with RNA polymerase and representative compounds in these two classes to help drive future potent drug design. In Table 1, we have summarized the comparative RNAP inhibition and efficacy information for some key clinical candidate rifamycins. 3. In vivo activity and PK/PD relationships Before providing a more in depth discussion of the pharmacokinetic/pharmacodynamic relationships of the rifamycins, some observations concerning their in vivo activity in rodent infection models of various analogs will be presented. Activity against M. tuberculosis mouse models will be presented when available, but in many cases the in vivo efficacy was determined in models of S. aureus. It should also be noted that the streptovaricins (Figure 3) have been reported to have good activity in vivo against M. tuberculosis.165 Among the earliest rifamycin natural products isolated or synthesized, rifamycin SV (Figure 2) quickly stood out due to its activity, especially when administered subcutaneously, in experimental TB models in rodents.14,166 Rifamycin S (Figure 7) was half as potent as rifamycin SV, and neither rifamycin B (Figure 2) or rifamycin O (Figure 7) had any significant activity.127 In a staph infection model a series of rifamycin B amides and hydrazides were

compared to rifamycin SV, and the diethylamide, diisobutyl amide, and piperamide were all several fold more potent than rifamycin SV, both subcutaneously and orally, as were several hydrazides.11 Comparison of rifamycin B diethylamide (rifamide, Figure 2) directly with rifamycin SV in a variety of mouse M. tuberculosis models consistently indicated that rifamide was at least three times more potent in vivo than rifamycin SV.167 3-Amino substituted analogs of rifamycin SV also had enhanced oral activity.128 For example, 3-morpholinorifamycin SV was four times more potent orally than rifamycin SV administered subcutaneously in a mouse M. tuberculosis model. As noted previously, a major advance was the discovery of the rifamycin hydrazones, in particular, rifampin (Figure 1). In a S. aureus infection model, rifampin administered orally was over 500 times more potent than rifamycin SV when both were administered orally (when both were administered subcutaneously rifampin was still over 100 times more potent than rifamycin SV).166 Rifampin was also quite effective orally in animal models of M. tuberculosis infection, being among the most potent of the antitubercular drugs available.2,166 Rifapentine (Figure 1), the pentyl analog of rifampin, was even more potent in vivo than rifampin.7,10 In the initial report comparing rifampin and rifapentine in experimental models of mouse TB infection, rifapentine was five to six times more potent than rifampin.88 This high level of activity, due in large part to the longer half-life of rifapentine, was demonstrated in a number of M. tuberculosis animal models, wherein rifapentine was shown to be highly effective with once weekly dosing in combination with a number of other anti-TB drugs.168e171

Figure 18. C-25 Substituted rifamycin analogs.

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Figure 19. Structure of the rifampin-quinolone hybrid CBR-2092.

As mentioned previously, oximinorifamycin analogs also had good activity in vitro against M. tuberculosis.90 Although the only data presented in vivo was against a mouse S. aureus infection, it is clear that some of these analogs, e.g., the methyloxime of 3-formylrifamycin SV, were quite potent when administered orally.90 The long-acting azinomethyl rifamycin derivative FCE 22250 (3, Figure 9) was much more potent against TB in a mouse infection model (similar activity seen at one-tenth the cumulative dose of rifampin) even though it was less effective by about three-fold than rifampin in a S. aureus mouse experiment.94,98 In terms of compounds wherein the C-3 and C-4 substituents are connected to form a five-membered ring, the imidazole 9 (Figure 11) wherein R ¼ piperidine was comparable in potency to rifampin when administered orally in a mouse TB infection model whereas the corresponding N-methylpiperazine was inactive.115 Much more interesting were the spiro-piperidyl-rifamycin analogs (10, Figure 12) as exemplified by rifabutin (Figure 1). Early reports showed the class as a whole was more potent than rifampin, and rifabutin was three-fold to seven-fold more potent than rifampin in murine TB infection models.6,116 Rifabutin was also shown to be effective in preventing infections in a mouse TB prophylaxis model.172 In terms of the homologated rifabutin analogs 11 shown in Figure 12, the only one reported to show oral activity in a mouse S. aureus model comparable to rifabutin was the isobutyl derivative (11 wherein R ¼ i-Bu and n ¼ 2).125 In terms of rifamycin analogs with the C-3 and C-4 substituents joined to create a six-membered ring, the simplest analog rifazine (1, Figure 8) was about twice as potent when administered orally as rifamycin SV administered subcutaneously in an experimental TB Table 1 Key comparative RNAP inhibition and efficacy information for the most important clinical candidate rifamycins. Rifamycin

E. coli RNAP EC50 (mg/mL)

M. avium RNAP EC50 (mg/mL)

MTB MIC50 (mg/mL)

Rifampin

0.07*

Rifapentine Rifabutin

0.10* <0.5y <0.5y <0.5y

Rifalazil

0.13*

0.20*

0.15x 0.125** 0.04** 0.06x 0.016** 0.004**

NA NA

(NA: data not available). * Fujii et al. and references cited therein.75 y Xu et al.291 x Burman et al. and references cited therein.188 ** Hirata et al.292

infection model.128 When compared directly with both compounds administered orally in a S. aureus infection, rifazine was 27 times more potent than rifamycin SV.166 The 30 -hydroxy-50 -aminobenzoxazinorifamycin derivatives (Figure 14) were even more promising with many derivatives proving more active than rifampin in a mouse TB infection model.131 Good activity was also seen in S. aureus models.131,173 Of highest interest among the initial compounds was rifalazil (Figure 2) which was clearly more potent than rifampin in vivo including against some rifampin-resistant strains.5,7,174,175 One study indicated that rifalazil at a 3-fold lower dose than rifampin in a mouse TB survival model was still more efficacious than rifampin.134 Another study comparing rifalazil, rifampin, rifapentine, and rifabutin indicated that rifalazil was the most effective against TB in mice as measured by bacterial load reduction.176 Similarly, a number of longer term mouse M. tuberculosis studies in combination with other agents used to treat TB indicated the same level of cure could be achieved with shorter (at least two-fold) duration of treatment with rifalazil as compared to rifampin.177e179 The newer benzoxazinorifamycins reported by ActivBiotics (Figure 15) also show good activity in vivo, though most of the studies have been against either S. aureus or chlamydia infections.16,17 Some of these compounds were even more potent than rifalazil and also had reasonable activity against some rifampinresistant strains.180 For example, ABI-0418 (Figure 15) at an IV dose of 20 mg/kg cured 11/30 mice and at an oral dose of 160 mg/kg cured 5/5 mice, as compared to 0/5 mice surviving with either of these doses when treated with rifampin in a mouse infection model with a rifampin-resistant strain.180 Similarly, ABI-0043 (Figure 15) was quite effective in rodent models of S. aureus, Streptococcus pneumoniae, and C. pneumoniae.181e183 The interesting Cumbre rifamycin-quinolone hybrid also showed very good activity in a series of S. aureus mouse models when administered intravenously, including some difficult to treat mouse catheter biofilm infections.184 Some exciting recent results from researchers at Johns Hopkins University indicate that the treatment duration of TB in the clinic could be dramatically reduced if higher doses of the rifamycins could be employed.185e187 In one study, the authors showed stable cure after four months of treatment in a mouse TB model when a twice weekly combination of rifapentine and either isoniazid or moxifloxacin was used.185,186 In the same study the standard daily therapy with rifampin, isoniazid, and pyrazinamide required six months of dosing to achieve similar results. In another study

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showing the superiority of rifapentine and moxifloxacin dosed either daily or thrice weekly to rifampin and isoniazid dosed daily, after just two months of treatment, the rifapentine/moxifloxacin combinations were culture negative for TB whereas the rifampin/ isoniazid combination still had significant levels of M. tuberculosis present.187 The enhanced activity of the rifapentine combinations appeared mainly due to greater rifamycin exposure when the rifapentine is administered more frequently than once weekly.187 The authors suggest that with daily or thrice weekly administrations of rifapentine and moxifloxacin it might be possible to reduce the duration of tuberculosis treatment in the clinic from six months down to three months.185,186 The question is whether such high doses of rifapentine would be tolerated in patients. With even more potent rifamycin analogs with good PK (good oral bioavailability, long half-life and low protein binding) and that are well tolerated, one would predict from these studies that the duration of treatment could even be shortened beyond that. Determination of the specific pharmacokinetic/pharmacodynamic parameters that drive rifamycin efficacy in patients has been difficult due to a number of reasons including: the drugs are always used in combination therapy, different rifamycins have different degrees of protein binding, and there are two phases in the treatment (an initial phase where there are large numbers of actively metabolizing and dividing bacilli, with many being extracellular, and a second phase after two weeks of treatment wherein it is now necessary to sterilize bacteria probably within white blood cells that are mostly dormant and only metabolizing for short periods of time).188 There have been a number of experimental models investigated to explain the excellent sterilizing activity of the rifamycins and there are indications that rifampin is particularly effective at killing those bacilli that are dormant for much of the time.4,189 The cumulative evidence suggests that Cmax/MIC correlates best with rifamycin efficacy188 though one study found that AUC/MIC gave a slightly better correlation than Cmax/MIC with rifampin in a murine aerosol infection model (T/MIC gave the worst correlation).190 Probably the most definitive PK/PD work was reported recently by Drusano et al. Their work indicates that the microbial killing by rifampin was related to AUC/MIC whereas the prevention of resistance was related to a free Cmax/MIC ratio being greater than 175.191 Their recommendation for the design of new rifamycin analogs was to prepare compounds that 1) allowed for efficient entry of the analog into M. tuberculosis, 2) had a long post antibiotic effect, and 3) can achieve a free Cmax/MIC of >175. One caveat here is whether other rifamycins would have the same PK/PD driver as does rifampin, but that remains to be investigated. 4. Pharmacokinetics The emphasis in this section will mainly be on ADME (absorption, distribution, metabolism and elimination) characteristics of compounds which have proceeded forward into clinical trials since that is where most of the useful data can be found. There is also a good review available comparing the PK of the major marketed rifamycins, namely rifampin, rifapentine, and rifabutin.188 Modulations of CYPs and drugedrug interactions will be discussed separately in the next section of this review. The initial rifamycin brought to the market, rifamycin SV (Figure 2), had very poor absorption requiring 50 mg/kg doses in dogs to observe any appreciable drug levels (no detectable blood levels in man with a dose of 500 mg), and thus was only used intramuscularly or intravenously in TB patients.14 It is 80e95% protein bound, and has a half-life in man of one to two hours.14 The compound does have a high volume of distribution, including a high concentration in the liver, and is mainly excreted via the bile. Rifamide (Figure 2), another early rifamycin brought to clinical trials, had slightly better PK than

rifamycin SV, giving about three-fold improved blood levels than rifamycin SV when administered orally to mice (and thus explaining its somewhat improved efficacy in murine S. aureus models); however, even at one gram oral doses in man, no appreciable blood levels were observed in some of the subjects.167 Administered intramuscularly or intravenously, rifamide had marginally better PK than rifamycin SV (half-life in man of two to three hours), and like rifamycin SV it was widely distributed and was mainly (80%) excreted in the bile largely as the intact antibiotic.167 Because of the poor oral absorption and relatively short half-life in man, rifamycin SV and rifamide were quickly replaced in clinical use by rifampin. Rifampin is rapidly orally absorbed (tmax ¼ 1.5e2.0 h at the typical 600 mg human dose) which is faster than rifabutin and rifapentine, and has an oral bioavailability of about 68%.2,188 Rifampin has a serum half-life in man of two to five hours, and is about 80% bound to serum proteins.192,193 The Cmax is 8e20 mg/mL following a 600 mg oral dose, and there is a modest food effect in terms of a decrease (6%) in AUC and more marked (36%) decrease in Cmax.188 Rifampin is widely distributed to most tissues and mainly excreted in the bile where the C-25 desacetyl derivative (from hydrolysis of the corresponding acetate), forms as the main metabolite (which still maintains useful antimycobacterial activity) along with the 3-formylrifamycin SV metabolite derived from hydrolysis of the rifampin hydrazone.188,192,194 The C-25 desacetyl metabolite is apparently formed via human liver B-esterases.194 About 13e24% of rifampin is excreted unchanged via the kidney.195 Small amounts of rifampin quinone, which has the rifamycin S (Figure 7) core but with the C-3 side chain of rifampin, has also been reported as a minor metabolite, but it is also an air oxidation degradation product of rifampin so that might be the source of the quinone. Although not strictly a pharmacokinetic parameter, an important contributor to efficacy and pharmacodynamics is the long post antibiotic effect (PAE) of rifampin (68 h when tested against M. tuberculosis at its peak serum concentration after a two hour exposure at 16 mg/mL).196 Rifapentine (Figure 1) was brought forward into the clinic as a more potent and longer-acting rifamycin than rifampin. Indeed, rifapentine has 70% oral bioavailability and a half-life of 13.2 h in human volunteers, clearly much longer than that of rifampin.10,188,197 It has a tmax ¼ 5e6 h and a Cmax ¼ 8e30 mg/mL at a 300 mg dose in man; however, it is nearly 98% bound to serum proteins.10,188 There is a 40e50% increase in AUC when given with food, though with the infrequent dosing schedule generally used in TB patients (600 mg twice weekly versus the daily dosing typical with rifampin) no drug accumulation would be expected.198 Tissue levels for rifapentine generally exceed plasma levels, unlike rifampin where they are more similar.10,188 About 70% of rifapentine is cleared via the biliary tract versus 17% in the urinary tract, with the major metabolite being 25-desacetylrifapentine, which is active against TB, and the minor metabolite being the 3-formylrifapentine derivative, again similar to what is seen with rifampin.10,188 Like rifampin, rifapentine has a long post antibiotic effect (75 h against M. tuberculosis after a two hour exposure at a concentration of 10 mg/mL).199 Given its lower MICs and longer half-life than rifampin, one would have predicted better efficacy in the clinic; however, it is clear that high protein binding and low concentration of free drug have limited its effectiveness.188,200 Indeed, it has been suggested that a 1200 mg dose of rifapentine would be more effective, and at least as single doses, the pharmacokinetics and preliminary safety have been evaluated in man.200,201 The pharmacokinetic properties of other long-acting rifampin analogs have also been studied. FCE 22250 (3, Figure 9) had a similar Cmax but three times longer half-life than rifampin when both were administered orally at 10 mg/kg in mice.89,90 More information is available on the related azinomethyl rifamycin analog rifametane (4, Figure 9). In mice, rats, dogs, and monkeys, rifametane had

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excellent oral bioavailability and significantly longer (at least threefold) serum half-lives than rifampin.202 In a phase I trial comparing rifametane and rifampin at 150 mg, both compounds had similar Cmax and tmax; however, rifametane had a six-fold longer half-life and seven-fold higher AUC.203 When the two rifamycins were compared at 300 mg oral doses, the Cmax for rifametane was almost two-fold that of rifampin, its half-life and AUC were about sevenfold that of rifampin and its half-life.204 Rifamycin analogs wherein the C-3 and C-4 substituents are linked to form a five-membered ring also have been shown to have interesting PK properties. rifaximin (Figure 1), presumably due to its formation of a zwitterionic species in the stomach, was not absorbed in rats, dogs, or man when administered orally, but was eliminated mainly intact in the feces after 72 h.113,205 These features, along with its potency against gut organisms, were successfully utilized to develop and market rifaximin for gastrointestinal diseases.8 Other five-membered ring analogs had better absorption. For example, the imidazole compound 9 (Figure 11) wherein R is piperidine had quite a high Cmax and AUC when administered orally to mice.115 This led to the spiro-piperidylrifamycins 10 (Figure 12) leading to the n-butyl analog (10 wherein R1 ¼ n-butyl and R2 ¼ R3 ¼ H) and rifabutin (Figure 1), which in the initial report showed the most promising PK in terms of relatively high AUC and Cmax after oral administration in mice.116 Rifabutin showed excellent oral bioavailability in rats (>98%) when administered at 25 mg/ kg; however, the oral bioavailability in rats was only 44% when the compound was administered at 1 mg/kg suggesting significant first-pass metabolism at lower doses.206 In man at the usual dose of 300 mg the oral bioavailability is only 20%, with a tmax of 2.5e4.0 h and Cmax of 0.2e0.6 mg/mL; however, the half-life of rifabutin is quite long in man at 16e69 h.6,115,18,76,105,176 There is no food effect on the AUC or Cmax though the tmax is increased, and protein binding at 70% is less than that of rifampin to human serum proteins.188 Rifabutin is well distributed throughout the body and is especially concentrated in the lungs. 6,207 About 50% of the dose was eliminated in the urine, including a significant amount of intact drug.115,208 Numerous metabolites in animals and man have been observed with rifabutin, with the active C-25-desacetyl derivative again as a major urinary metabolite generated by hepatic B-esterases.194,209 Additional metabolites noted in man were oxidation products to give the C-27-O-desmethylrifabutin, 20-hydroxyrifabutin, 31-hydroxyrifabutin and 32-hydroxyrifabutin analogs (all being at least 10-fold less potent than rifabutin).115,206,208,209 Rifabutin was reported to have a similar post antibiotic effect in M. tuberculosis as rifampin.210 The importance of PK was noted in one paper where lower plasma concentrations of rifabutin were correlated with clinical failure due to the development of rifamycin-resistant mycobacteria.211 The pharmacokinetics of rifamycin analogs with the C-3 and C-4 groups joined to form a six-membered ring have also been reported. For example, rifazine (1, Figure 8) had somewhat better oral absorption and serum half-life than rifamide and rifamycin SV in dogs.212 Rifazine was well distributed in most tissues, with the exception of the brain, and was especially concentrated in the liver and intestine in rats; there was very little excretion via the urinary tract.212 The initial PK reported on the 5-aminobenzoxazinorifamycins 13 (Figure 13) in rats looked somewhat promising.130 The more interesting series, the 30 -hydroxy-50 -aminobenzoxazinorifamycins (Figure 14) showed higher tissue levels of drug but low plasma levels after oral administration in mice, unlike rifampin and rifabutin which showed good levels in both plasma and tissue.7,131 The primary compound of interest to arise from these studies, rifalazil (Figure 2) had a high volume of distribution and produced tissue levels in rats up to 200 times those in plasma. The half-life in the rat

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was 16e20 h and in the dog was about 50 h.16,17,213 In the dog, rifalazil showed non-linear pharmacokinetics, and protein binding was very high (>99%) in both dogs and rats.213 In human trials, the half-life was very long, 60e100 h.16,214 AUC and Cmax were increased with food while intersubject variability decreased.215 In vitro metabolism studies suggested that dog most resembled man with the C-25-desacetylrifalazil and C-30-hydroxyrifalazil being the suggested metabolites, the latter arising via a cytochrome P450 mechanism.216 Actual studies in dogs and man indicated that indeed the major metabolite was again the C-25-desacetyl species (shown to be equivalent in potency, at least against S. aureus strains); however, whereas the other urinary metabolites in the dogs were C-30-hydroxyrifalazil and C-25-desacetyl-C-30hydroxyrifalazil, in man the other major urinary metabolite was actually C-32-hydroxyrifalazil.213,217 Interestingly, C-32-hydroxyrifalazil was only half as potent as rifalazil against M. smegmatis in vitro, being twice as potent as the C-25-desacetylrifalazil metabolite and 16-fold more potent than rifampin.217 It was determined that a B-esterase was responsible for the formation of the C-25desacetylrifalazil metabolite, and that CYP3A4 caused the formation of the C-32-hydroxy metabolite.218 In animal studies of the rifalazil analog ABI-0043 (Figure 15), the compound also had a high volume of distribution but a shorter halflife with a predicted human half-life of 12e20 h.16,17 ABI-0043 appeared to be stable when incubated with human liver microsomes and, since it is already a C-25-hydroxy derivative, would not be susceptible to the normal C-25-acetate hydrolysis pathway seen with the marketed rifamycins.16,17 In summary, it has proven possible to improve on the PK properties of rifampin. In particular, rifapentine is a longer-acting rifamycin requiring only twice weekly dosing. The half-lives of rifabutin and rifalazil are also significantly longer than that of rifampin suggesting the possibility of intermittent dosing. The rifamycins (with the exception of rifaximin) are generally widely distributed in the body, and rifabutin and especially rifalazil give higher tissue levels than plasma levels. However, while rifabutin has lower protein binding than rifampin, both rifapentine and rifalazil have very high protein binding, a concern for both compounds since presumably the efficacy is related to free drug concentrations. The major metabolite of the rifamycins is typically the C-25-hydroxy derivative obtained from hydrolysis of the C-25-acetate; however, this metabolite usually retains much of the activity of the parent and can even in some cases (e.g., ABI-0043) be the actual compound that is dosed. Rifabutin and rifalazil, and presumably their analogs, are also metabolized on the methyl groups of the ansa side chain with the other major rifalazil urinary metabolite, C-32-hydroxyrifalazil, also being similar in potency to the parent compound. Thus, overall the rifamycins tend to have good pharmacokinetic properties with the exception of the cytochrome P450 interactions which will be discussed in the next section. In Table 2, we have summarized the comparative PK/PD information for some key clinical candidate rifamycins. 5. Drugedrug interactions One major downside to the rifamycins used to treat TB is their many drugedrug interactions. Most of the interactions result from the ability of the marketed rifamycins to induce metabolic enzymes, in particular cytochrome P450 3A4 (CYP3A4), in the liver and small intestine.188,219 The clinical pharmacokinetic interactions with rifampin are numerous, and include effects on analgesics (e.g., morphine), antidiabetic drugs (e.g., sulfonylureas), antibacterials (e.g., doxycycline), antifungal drugs (e.g., ketoconazole), antivirals (e.g., nelfinavir and efavirenz), psychotropic drugs (e.g., diazepam and buspirone), cardiovascular drugs (e.g., verapamil, simvastatin, and warfarin), hormones (e.g.,

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Table 2 Key comparative PK/PD information in man for the most important clinical candidate rifamycins. Rifamycin

Bioavailability (%)

Cmax (mg/mL)

Cmax/MIC ratio

Serum half-life (h)

Serum protein binding (%)

Rifampin (600 mg) Rifapentine (600 mg)

68* 70y

10.0* 15.0*

67* 375*

85* 97*

Rifabutin (300 mg) Rifalazil

20* w50x

0.45* 0.13(5 mg)** 0.41(25 mg)** 0.70(50 mg)**

7.5* 33(5 mg)** 103(25 mg)** 175(50 mg)**

2e5* 14e18* 13.2y 32e67* 61(25 mg)** 109(50 mg)**

71* 99yy

(NA: data not available). * Burman et al. and references cited therein.188 y Global Alliance for TB Drug Development and references cited therein.197 x Fernandes et al.293 ** Rose et al.285 yy Global Alliance for TB Drug Development and references cited therein.214

prednisolone), and immunosuppressants (e.g., cyclosporine).219 The induction of CYP3A4 generally leads to the enhanced metabolism of many other drugs resulting in a lower AUC and/or Cmax of the other drug such that a dosage adjustment may be necessary or else the other drug is rendered ineffective. Rifampin also induces some drug transporter proteins, such as intestinal and hepatic P-glycoprotein, and so, for example, has a clinically significant interaction with digoxin.219 Thus, rifampin has pronounced effects on many orally administered drugs that are metabolized by CYP3A4 and/or are transported by P-glycoprotein. Particularly problematic are drug interactions in AIDS patients because of the pronounced interaction of rifampin with protease inhibitors (e.g., a 92% decrease in the AUC of indinavir when the standard daily dose of 600 mg rifampin is employed), not to mention the increase in metabolism of other drugs (e.g., fluconazole and itraconazole) typically utilized to treat opportunistic infections.219 Rifampin also induces the activity of CYP1A2, CYP2C, and CYP2D6.188,219 For example, its interaction with CYP2C9 results in a reduction in the plasma level of warfarin for patients who also take that medicine.219 Unfortunately, rifampin also interacts with some of the drugs that could be used in combination to treat TB. For example, a recent study combining rifampin, isoniazid and moxifloxacin in patients showed about a 30% decrease in the exposure of moxifloxacin.220 Rifapentine also induces the hepatic microsomal enzymes CYP3A4 and CYP2C, although far fewer clinical drugedrug interaction studies have been conducted with rifapentine than rifampin.188 However, the effect with rifapentine is more modest than with rifampin, particularly when rifapentine is administered with a twice weekly regimen.10,188,221 For example, with rifapentine administered 600 mg twice weekly, the AUC of indinavir was reduced by 70%. As with rifampin, other CYP inhibitors did not affect the plasma levels of rifapentine, since neither are extensively metabolized by CYPs.188 Rifapentine also does not induce its own metabolism.10 While rifampin was a modest inducer of CYP2D6, rifapentine did not seem to have much effect on this particular cytochrome.10,221 Rifabutin both induces and is metabolized by CYP3A4, thus its drugedrug interactions are a bit more complex. Rifabutin does have enzyme-inducing properties in man, though the effects appear to be much less than those of rifampin and rifapentine.188,222e224 For example, in terms of interaction with indinavir, there was only a 34% decrease in the AUC of indinavir when co-administered with a 300 mg daily dose of rifabutin.188 In vitro studies with primary human hepatocytes also indicate that rifabutin is a weaker CYP inducer than rifampin or rifapentine with little or no activity at CYP1A2.221,225 On the other hand, unlike rifampin and rifapentine, since rifabutin is metabolized by CYP3A4, co-administration with CYP3A inhibitors, such as the HIV protease inhibitors, can increase its

concentration significantly. For example, co-administration with nelfinavir increased the AUC of rifabutin nearly 300%.188 Nevertheless, success has been noted in the use of rifabutin in the treatment of AIDS patients infected with M. tuberculosis, and since rifabutin has significantly less CYP induction than rifampin, it may be the preferred drug in this patient population.226 An even more promising series of rifamycin analogs in terms of minimizing CYP induction is with rifalazil and its analogs. In the rat and the dog rifalazil did not appear to induce any enzymes.227 Additional studies with rifalazil, ABI-0043, and several other analogs indicated that this class did not induce CYP3A4 in cell culture using human hepatocytes or in animals in ex vivo experiments.16,17,180 Rifalazil was also not an inducer of hepatic cytochrome P450.227 Induction of CYP3A4 by rifampin, and presumably rifapentine and rifabutin, is mediated by the pregnane X receptor (PXR), a human orphan nuclear receptor.188 PXR binds to a response element in the CYP3A4 promoter and is activated by a range of drugs, including rifampin.228 More specifically, rifampin binds to PXR creating a complex that then forms a heterodimer with the retinoid X receptor. This heterodimer binds to a DNA response element in the CYP3A4 promoter thus enhancing CYP3A4 transcription and ultimately the synthesis of CYP3A4 protein itself.219 Rifampin induces the expression of several other proteins in a similar manner. PXR is also involved in the regulation of action of other cytochromes, including CYP1A1, CYP2C8 and CYP2C9, as well in the regulation of cholesterol transport.219,229 Rifampin and rifamycin SV have also been shown to interfere with hepatic bile salt and organic anion uptake via inhibition of the human liver organic anion transporting polypeptides OATP1 and OATP2.230,231 The inhibition of OATP2 (also called OATP-C and OATP1B1) by rifamycin SV has also been linked to the hyperbilirubinemia seen in the clinic with this drug.232 In vitro studies also indicated that the expression of OATP2 enhances cellular accumulation of rifampin into HeLa cells and potentiates PXR activation.233 The interaction of rifampin with a variety of hepatic transporters and the interaction with PXR is a complex regulatory process in human hepatocytes which can profoundly impact the metabolism of drugs co-administered with rifampin.234e236 In summary, the rifamycins exhibit drugedrug interactions with many other drugs, much of this activity being mediated by PXR, with CYP3A4 interactions being particularly problematic. However, it is possible to develop compounds with improved properties relative to rifampin. In fact, the relative potency towards CYP3A induction is rifampin > rifapentine > rifabutin > rifalazil. Thus, concentrating on analogs in the rifabutin and rifalazil class should help to minimize CYP interactions, although one has to be aware of possible effects on the rifabutin analog metabolism by CYP inhibitors used in

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co-therapy. A number of model systems have been employed to predict cytochrome P450 induction and drugedrug interaction potential of the rifamycins. One in vitro system using human primary hepatocytes appears to have some promise.221 Other investigators have also utilized ex vivo assays using rabbits, noting the closer similarity of rabbit CYP3A4 isoform than the rat isoform to human CYP3A4.237 A more complicated model of CYP3A4 induction uses chimeric mice with a humanized liver.238 The realization that cytochrome P450 induction, as well as P-glycoprotein and a number of transporters, is regulated by rifamycin binding to PXR opens the possibility of newer in vitro assays for predicting drug interactions in man that should be much more reproducible, easier and cost effective to run.228,239 Indeed, rifampin has been evaluated and its potency in terms of CYP3A induction in hepatocytes and in vivo seems to be well correlated to its binding in the PXR assay where it was one of the most potent compounds examined in two separate studies.240,241 Such assays are now also becoming commercially available, in particular by Puracyp Inc., a new biotech company with proprietary technology and high-throughput screens for PXR binding and activation.239e243 Thus, it would be worthwhile to investigate this technology as a more robust, reproducible, and higher throughput method for evaluating CYP3A induction by rifamycin analogs. One caveat to testing rifamycin analogs, particularly at higher doses, is that the compounds can form aggregates and micelles that could give false positive results; thus, it is advisable to check for this particularly with the less soluble analogs.28,244 Indeed, non-specific binding of rifamycins has been noted at higher concentrations.245 6. Toxicity Most of this section will discuss the toxicities seen in TB patients, particularly those side effects that are dose-limiting; however, some mention of safety studies reported with rifamycins either preclinically or in clinical trials for agents that did not get to market (or are no longer on the market) will be mentioned as well. In the early years of rifamycin drug discovery, analogs for further development were apparently selected based on a combination of activity and toxicity as determined by an acute (single dose) LD50 in rodents.83,166 This rather crude (by today's standards) safety estimation is probably not very relevant to the clinical toxicities actually observed with the rifamycins but was apparently at least part of the initial selection process for rifamycin SV, rifamide, and rifampin. A number of systemic effects in man were observed following treatment with rifamycin SV, the first rifamycin introduced to the market, foreshadowing some of the safety issues that would be a concern with later rifamycin agents. In particular, albeit at very low incidence (less than one percent), several cases of allergic reactions and fever were noted.14 There were also effects on the liver reported, with several cases of jaundice at higher concentrations of rifamycin SV.14 Later studies showed an effect of rifamycin SV on glutathione depletion and generation of reactive oxygen in liver microsomes, suggesting that these could be contributing, at least partially, to its liver toxicity.246,247 As mentioned in the previous section, inhibition of OATP2 by rifamycin SV has been linked to some of the liver effects noted with the agent in man.232 Limited safety studies have been published with rifamide; however, it would appear to be reasonably well tolerated, with a similar profile and toxicity as rifamycin SV.248 Many more studies and much more solid information is available for rifampin.188,195,249e251 Rifampin is actually quite well tolerated when given as the normal daily oral dose of 600 mg to TB patients.249e251 The major adverse side effects can basically be divided into two types, hepatotoxicity and immunoallergenicity.251 Treatment-limiting toxicity is most typically associated with a flu-

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like syndrome.188 In terms of hepatotoxicity, rifampin causes changes in liver function but the risk of serious injury is small in patients without a preexisting history of liver damage.249,252 Although there have been reports of hepatitis and jaundice in TB patients being treated with rifampin in combination with isoniazid or pyrazinamide, the actual incidence of hepatotoxicity due to the rifampin (1.1%) in these combinations is less than that from isoniazid or pyrazinamide.252e254 Rifampin has even been used clinically to treat pruritis in patients with primary biliary cirrhosis.255,256 Allergic or hypersensitivity reactions are relatively infrequent with rifampin particularly when the typical daily dose of 600 mg is employed.188,249,251,257 The flu-like syndrome is characterized by fever, chills, and malaise, as well as sometimes headache, dizziness, or bone pain.249 The episodes typically develop one to four hours after treatment and usually resolve within several hours. The incidence of the flu-like syndrome with rifampin is associated with dose and especially intermittent therapy.251,257 Treatment twice weekly with 1200 mg or 900 mg of rifampin produced 16% and 2.5% respectively of the flu-like syndrome in TB patients in some early studies.257,258 In a larger study, the syndrome developed in 36e44% of patients on 900e1200 mg of rifampin given once a week by the sixth month, and in 54% of patients administered 900 mg once a week by the twelfth month.257 Other studies found that doses of rifampin of 1200e1800 mg caused the flu-like syndrome in about 36% of patients if given once weekly as compared to about 19% if given twice weekly.249,257 Doses of 900 mg produced the effect in about 27% of patients with weekly dosing and 8% with twice weekly dosing. The 600 mg dose gave only 10% and 4% of the flu-like syndrome with once weekly and twice weekly dosing, respectively.257 Switching to daily-dosed rifampin usually results in a disappearance of all symptoms.250,251 It should be noted that even with intermittent dosing, it is uncommon to see the flu-like syndrome in the first three months of therapy.250 Thrombocytopenia, hemolysis and renal failure can also occur in some patients, again mostly associated with intermittent rifampin dosing, but this is actually quite rare.188,250,251,259e261 The thrombocytopenia and hemolysis are thought to be mediated by antigen-antibody complexes. The possible hapten is 3-formylrifamycin SV, a metabolite of rifampin arising from the hydrolysis of the C-3 hydrazone, with the reactive antigenic site being the C-3 aldehyde.257 Although the flu-like syndrome could be a direct toxic effect since it is more frequent with higher doses and when blood levels of rifampin are higher, it is more plausible that this effect is due to circulating immune complexes.188 Antibodies develop against rifampin with intermittent dosing and at higher doses, usually only after several months of therapy, although rifampin antibodies are not always associated with the flu-like syndrome or the more severe hypersensitivity reaction that fortunately only rarely occurs in patients.188,249,257,258,262e265 Once weekly dosing or a prolonged interruption in therapy permits the development of a more potent immune response against rifampin upon rechallenge.188 Assuming rifampin is a weak immunogen, daily dosing would produce tolerance whereas intermittent dosing could cause sensitization. Unlike the more severe anaphylactic reactions which do appear to be IgE related, the flu-like syndrome effects do not seem to be mediated by IgE.257,266 Instead, the antibodies associated with the flu-like syndrome are of the IgG or IgM class and may act by fixing complement in the blood or on the surface of the endothelial cells, or else by binding on the surface of cytokine-producing cells.257 Rifampin has been shown to have a number of immunomodulating properties. One study showed a modest increase in IL-1a and TNF release in human monocyte supernatants upon treatment with rifampin (and rifamycin SV).267 Another study in human monocytes actually showed that rifampin inhibited the production of IL-1b and

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TNF-a but significantly increased the secretion of IL-6 and IL-10.268 Other studies showed that at clinically relevant levels, CD1b expression was increased.269,270 In addition, rifampin appeared to increase cytokine-induced nitric oxide production.271 A very recent study in TB patients followed for several months indicated that rifampin exposure correlated to IFN-g response and that this response may also be related to treatment outcome.272 In early reports, rifapentine was described as less toxic than rifampin.88 In the clinic overall rifapentine seems better tolerated than rifampin, though that may in part be due to the higher protein binding activity of rifapentine relative to rifampin. For example, once weekly rifapentine was better tolerated than twice weekly rifampin.188,273 While the hepatotoxicity seen with rifapentine is similar (and certainly no worse) than that seen with rifampin, it would appear that the flu-like syndrome with intermittently dosed rifapentine is significantly less of an issue than it is with rifampin, being rarely seen with once weekly regimens of rifapentine.188,197 This may occur because of a reduced immune reaction to rifapentine or because rifapentine has a longer half-life so that the immune system has a longer exposure to rifapentine and a shorter duration in which there is no measurable rifamycin present than with twice weekly rifampin dosing. Once weekly administration of rifapentine at 600 mg, 900 mg, and 1200 mg have been studied in TB patients, and it would appear that the 600 mg and 900 mg doses are well tolerated, with more study of the 1200 mg dose being recommended.274 On the other hand, a study where a thrice weekly treatment of TB patients with rifampin, isoniazid, pyrazinamide, and streptomycin for two months was followed by thrice weekly rifampin or once weekly rifapentine showed that the rifapentine had overall more adverse events than the follow-up rifampin regimen.275 Limited information is available on the side effects seen with the azinomethyl rifamycin rifametane (4, Figure 9). In a phase I study comparing rifametane and rifampin, overall both drugs were well tolerated at a 150 mg dose though there was a slightly greater increase of several liver enzymes with rifametane.203 In a separate phase I study comparing the two drugs, rifametane at a 300 mg single dose caused slightly elevated temperatures for several hours in several subjects, possibly a sign of the flu-like syndrome.204 Overall the rates and types of adverse events in the treatment of TB, especially in non-AIDS patients, seem similar between rifabutin and rifampin.6 However, whereas uveitis (inflammation of the iris), especially in AIDS patients, is a dose-limiting side effect seen with rifabutin, this is not observed with rifampin administration.188,276 Rifabutin treatment in TB patients is also more often associated with neutropenia and polyarthralgia.188,276 The adverse side effects seen with rifabutin are much more related to high dose treatment (>600 mg/day) than at the lower doses more typically used (300 mg/day), and are exacerbated in AIDS patients because the protease inhibitors that are co-administered also inhibit CYP3A leading to higher levels of rifabutin.188 Hepatitis has also been seen with rifabutin, but like rifampin, it is more due to the other TB drugs co-administered with the rifamycin.120 A TB trial comparing rifampin (600 mg/day) versus rifabutin (150 mg/day and 300 mg/ day), showed that while the 150 mg rifabutin dose was at least as well tolerated as rifampin, the 300 mg rifabutin arm had the most number of adverse drug events, though there was no statistically significant difference in terms of treatment-related adverse events between the three arms.276 In this trial the most severe adverse events were noted in the rifampin arm. The flu-like syndrome can also occur with rifabutin when intermittent treatment is employed. In a clinical trial comparing either 300 mg twice weekly or 600 mg twice weekly rifabutin, the 300 mg dose was well tolerated whereas the 600 mg dose had one patient (out of 14 subjects) exhibit the flu-like syndrome and four patients exhibit neutropenia.277 Rifabutin has also been studied extensively in the

treatment of M. avium, and overall it is not quite as well tolerated as rifampin.278 Part of the issue is that the macrolides typically coadministered with rifabutin may be elevating rifabutin serum concentrations, but there are examples where this is not the case.279e281 The serious side effects most commonly observed with rifabutin treatment in this patient population are uveitis, leucopenia, and polyarthralgia which are infrequently seen with rifampin.280e282 High dose treatment (600 mg/day) with rifabutin in M. avium patients seems most commonly associated with hematologic side effects, though there has been at least one report of a patient with a fever and hypersensitivity rash, and the most serious side effects at this dose were uveitis and polyarthralgia.283,284 The 300 mg/day dose was much better tolerated.283 Less safety information is available on rifamycin analogs with the C-3 and C-4 substituents linked to form a six-membered ring. The earliest analog, rifazine (1, Figure 8), was reported in preclinical safety studies in dogs to show clear evidence of liver toxicity.212 More information is available on rifalazil (Figure 2) which did proceed into clinical trials. In preclinical safety studies, rifalazil was reasonably well tolerated in rats and dogs, with some hematological changes and an increased liver weight, the no-observed adverse-effect level being 1000 mg/kg.285 In chronic studies in dogs the no-observed adverseeffect level was 300 mg/kg.285 Unfortunately, rifalazil was not nearly as well tolerated in people as it was in rodents and dogs. In a series of four phase I trials (two single dose and two multiple dose) in healthy human volunteers, rifalazil proved to be quite toxic, particularly in terms of the flu-like syndrome and leucopenia.285,286 In the initial single dose trial at 300 mg, rifalazil exhibited significant toxicity, showing numerous side effects, including flu syndrome in half of the subjects.285 The compound was better tolerated in the subsequent single dose trial at 30 mg and 100 mg; however, the 100 mg dose was still not very well tolerated with at least one of the eight subjects exhibiting the flu-like syndrome.285 The third trial was daily dosing at 5 mg/day or 25 mg/day intended for 14 days; however, daily dosing at the 25 mg/day dose was suspended because again too many side effects were seen, including many signs of the flu syndrome in most of the subjects. Even the 5 mg/day dose group showed some indication of the flu-like syndrome in essentially all of the subjects.285 In terms of number and severity of side effects, the 25 mg/day regimen was more than twice as toxic as the 5 mg/day regimen. The fourth trial examined 25 mg or 50 mg of rifalazil dosed weekly for four weeks. In this trial the incidence of side effects was reduced in number and severity relative to daily dosing. The 50 mg weekly dose was about twice as toxic as the 25 mg weekly dose; however, there was still a high incidence of the flu-like syndrome noted, with the majority of subjects in both groups still showing some signs of this syndrome.285 The other major side effect noted in these trials in healthy volunteers was leucopenia, which was again dose-related and more severe in the subjects dosed daily versus weekly where overall only one severe side effect was noted (at the 50 mg/week dose).285 The safety of rifalazil was also assessed in a phase II trial comparing daily rifampin with once weekly dosing of 10 mg or 25 mg of rifalazil. In this study in TB patients, rifalazil was actually tolerated better than in healthy human volunteers with no statistical significance in side effect profile between rifampin and rifalazil, possibly because the blood levels of rifalazil were lower than observed in the healthy volunteers at the same dose.286 However, it should be noted that even in this small study, the incidence of side effects in the 25 mg rifalazil arm was higher than the rifampin arm, and that one out of 16 of the patients on the 25 mg rifalazil arm exhibited clear signs of the flu-like syndrome.5,286e288 There was no evidence of an antibacterial effect with rifalazil in the study, but this is not surprising since the doses utilized are far below what was

P.A. Aristoff et al. / Tuberculosis 90 (2010) 94e118 Table 3 Key comparative DDI and toxicity information for the most important clinical candidate rifamycins. Rifamycin

CYP metabolism

Relative CYP induction

Flu-like syndrome

Rifampin

negligible*

strong*

Rifapentine Rifabutin Rifalazil

negligible* CYP3A4* NA

moderate* weak* none detected**

36e44% @ 6 mos of intermittent, high dosingy rare w/1/wk dosing* 7% @ 600 mg 2/wkx 67% @ 300 mg single doseyy 100% @ 5 mg/day, 25 mg/day or 50 mg 1/wkyy

* y x ** yy

113

Funding: This review was funded by a grant from the Global Alliance for TB Drug Development. Competing interests:

None declared.

Ethical approval: Not required.

Burman et al. and references cited therein.188 Martinez et al.257 Matteelli et al.277 Mae et al.227 Rothstein et al.16

needed in the animal efficacy studies.5,285,286 Due to the side effect profile of rifalazil, the development of it for TB indications was suspended.3 One hypothesis for the flu-like syndrome seen so readily with rifalazil is that it causes release of cytokines with evidence of increased levels of IL-6 in the blood.12 On the other hand there is a report that, at least in a mouse TB infection model, rifalazil actually blocked the increase in levels of IL-10 and TNF-a, and that IL-6 levels were beneath the limit of detection during the study.289 Also, rifalazil did not seem to influence IL-10 and TNF-a production in macrophages.289 Since the flu-like syndrome with rifalazil was seen with single dose administration, it is unlikely that antibodies are involved. One could examine this, along with rifampin and rifabutin, in a rabbit model of sensitization that was reported to show rifampin IgG antibodies.290 In conclusion, although the rifamycins currently used in clinical practice are actually reasonably well tolerated, their dose, and often their schedule, is limited by side effects, particularly the flu-like syndrome for rifampin. Rifabutin has more of a problem with uveitis than the other rifamycins. Including rifalazil, which has to date proven too toxic for effective use against TB in man, the potency relative to the flu-like syndrome appears to be rifalazil  rifampin  rifabutin  rifapentine. In Table 3, we have summarized the comparative DDI and toxicities for some key clinical candidate rifamycins. 7. Summary It is still quite possible to devise improved rifamycin analogs. Studies showing the potential of shortening the duration of treatment if higher doses of some of the current rifamycins could be tolerated also suggest that more potent (or less toxic) new rifamycin analogs might accomplish the same end. The improved activity against rifampin-resistant strains by the rifabutin analogs made by the Spanish group and the rifalazil analogs prepared at ActivBiotics give promise that further work in this area, especially if the information from co-crystal structures with the RNA polymerase is applied, should lead to even more promising analogs. The extensive drugedrug interactions seen with rifampin have already been somewhat ameliorated with rifabutin and rifalazil, and use of a PXR based screening assay should serve to identify even better analogs. The toxicity due to the flu-like syndrome is also an issue that needs effective resolution, particularly for analogs in the rifalazil class, and here it would be of interest to profile rifalazil and several of its analogs (e.g., ABI-0043 and perhaps ABI-0418) in relation to rifampin, rifapentine, and rifabutin in a variety of screens, particularly those that might relate to hypersensitivity or immunomodulatory processes.

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