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Recent advances in retrometabolic design approaches
Journal of Controlled Release 62 (1999) 209–222 www.elsevier.com / locate / jconrel
Recent advances in retrometabolic design approaches N. Bodor* Center for Drug Discovery, University of Florida, P.O. Box 100497, JHMHC, Gainesville, FL 32610, USA
Abstract The retrometabolic drug design approaches simultaneously incorporate structure activity (SAR) and structure metabolism (SMR) relationships in the design process. Two major approaches were developed, the chemical delivery systems (CDS), which allow chemical–enzymatic targeting of drugs via strategic sequential enzymatic activation of the inactive CDSs. On the opposite end of the retrometabolic design loop are the soft drugs (SD), which are designed to have highly improved therapeutic indeces by controlling their metabolism, after they achieve their therapeutic role. One of the most successful SD class is the ‘inactive metabolite approach’, where the design starts from an inactive metabolite of a drug. Its strategic manipulation yields an isosteric / isoelectronic drug analog, which is enzymatically deactivated to the very inactive metabolite at the desired compartment and with controlled rate. Overall, retrometabolic approaches represent a complex collection of chemical–enzymatic means for the design of safer drugs and for their controlled release. Most recent advances involve FDA approval of a soft steroid, as well as the first successful brain targeting of various neuropeptides and their brain-targeted analogs. 1999 Elsevier Science B.V. All rights reserved. Keywords: Drug design; Retrometabolic methods; Brain targeting; Redox targetor systems; Therapeutic index; Sequential metabolism
1. Introduction A very large number of promising drug candidates have failed to become drugs, due to the various toxic side effects they exhibit. The activity and toxicity aspects of a drug candidate are the major issues evaluated during the drug development process. These two major properties, the efficiency and safety, however, are generally studied separately, as the first aim of drug design is always the activity. But it is well-known that essentially the ratio between the activity and toxicity, that is, the therapeutic index is the most important property of a drug. In order to design active, safer drugs, one should *Tel.: 11-352-3928186; fax: 11-352-3928589. E-mail address: [email protected] (N. Bodor)
include structure metabolism relationships (SMR) (the safety aspect can very well be affected by metabolism) in addition to the structure activity (SAR) relationships. The combination of these two relationships, represent the retrometabolic drug design (RMDD) concepts. The general principles of retrometabolic drug design approaches, have been reviewed recently in various publications [1–6], and a biannual international conference [7] addresses the major developments in the field. Thus, here only a brief summary is given. The retrometabolic drug design approaches include two distinct methods to improve the therapeutic index of a drug (D). One, is the general concept of the chemical delivery system (CDS), which is defined as a biologically inert molecule containing the drug (D) in an appropriately modified form, that
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requires several (mostly enzymatic) steps during its conversion to the active drug, and that enhances drug targeting to a particular organ or site. Within this design process, the drug is chemically converted to an inactive precursor, which contains two types of attachments, the most important is the targetor (T), while modifier functions (F 1 ... F n ) will be used if necessary to optimize the chemical–physical properties of the molecule to achieve better delivery. Targeting is achieved by design: the CDS will undergo sequential metabolic conversions removing the modifiers and finally the targetor after this moiety fulfills its site or organ targeting role. In general, these methods represent true targeting and controlled drug release. The targeting and sustained release properties are controlled by design, based on various enzymatic systems present, either in the whole body or in specific sites. In general, various enzyme systems are involved, such as oxidative, reductive or hydrolytic enzymes. Examples are abundant in the literature, including brain targeting and controlled release of drugs and neuropeptides, targeting various drugs to the anterior segment of the eye, targeting to lungs and others [2,4,8–10]. The CDS approach is summarized in a simple form by the left hand side of the retrometabolic drug design loop shown on Fig. 1.
The other, opposite but equally successful approach in retrometabolic design, involves the soft drugs, as simplistically represented by the right-hand side of the loop [4,11,12]. As illustrated here drugs undergo multiple metabolism, including conversion to analog metabolites (D 1 ... D m ) having similar type of activity as D, different other metabolites (M 1 ... M k ) and reactive intermediates (I 1* ... I *n ), among which there are inactive metabolite(s) (M i ). One of the most important approaches in the soft drug design involves the ‘inactive metabolite approach’, whereby the design starts with an inactive metabolite of an active drug, followed by converting this inactive metabolite to an isosteric / isoelectronic analog of the lead drug (soft drug, SD), assuring thus, activity. The design of this soft analog (SD) is however done in such a way that the SD will metabolize in one-step back to the very inactive metabolite the design started with, without undergoing any other metabolism. This process happens after the drug achieves its therapeutic role at the site of action, and thus prevents the rest of the body to be exposed to the active drug or to various active or reactive metabolic products. One can see that the two approaches, essentially are opposite of each other, the CDS are inactive by
Fig. 1. The retrometabolic drug design (RMDD) loop.
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design, and activated strategically at the site of action, while the SDs are active, novel drugs which exert their desired activity at the applied site, however, they will be destroyed metabolically in a timely fashion, so they cannot effect the other sites in the body. One other difference, between the two approaches, is the type of enzymes generally involved in the strategic activation or the activation, respectively. While in the case of CDSs, various enzymes, including oxidative and reductive enzymes are also involved, in the design of soft drugs, the objective is to use preferentially hydrolytic enzymes, and to avoid oxidative processes.
2. Results and discussion
2.1. Loteprednol etabonate It would be informative to review a successful case of design of a new, important soft drug. This is prompted by the fact that loteprednol etabonate (LE), a soft steroid [13–20], has received on March 9, 1998, FDA approval as the active ingredient of two ophthalmic preparations, LotemaxE and AlrexE. Approval for the two products was received simultaneously, and in this way loteprednol became the only corticosteroid receiving FDA approval for all inflammatory and allergy related ophthalmic disorders, including post-surgical inflammation, uveitis, allergic conjunctivitis, giant papillary conjunctivitis (GPC), etc. As a start, it should be mentioned that corticosteroids, although the most important drugs to treat ocular inflammations and allergies, are contraindicated, as in addition to the general systemic and local corticosteroid side effects, in the eye, they also produce elevation of the intraocular pressure (IOP), that is, they cause glaucoma, in addition to provoking cataract. Thus, it was of utmost importance to design an active corticosteroid which is void of these serious side effects. Fig. 2 illustrates the major metabolic pathways of hydrocortisone, the simplest (natural) corticosteroid. The acidic metabolites are inactive, among which, cortienic acid, where the oxidation removed the 21 carbon atom, is one of the major metabolites excreted in the urine of man. This inactive metabolite was used as the starting point to produce various soft
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analogs by esterifying the cortienic acid in the 17b position, as well as, to introduce necessary lipophilic functions in the 17a position. Further modifications are common in the corticosteroid design, involving D1 double bond, halogen in 9a and / or 6a positions, and methyl or hydroxy groups in 16a or 16b positions. The changes critical to the soft drug design, thus are the modifications in the 17b and 17a positions. The general structure of the designed soft corticosteroid classes, the design process and metabolism are summarized in Fig. 3.
2.1.1. A brief history The first soft steroids of this kind were synthesized in the late 1970s followed by a systematic synthetic study performed in collaboration with Otsuka Pharmaceutical Company in 1980–1981. From the beginning our approach was concentrating on using 17a carbonates, instead of 17a esters, in order to assure enhanced stability and thus prevent mixed anhydride formation from 17a esters following hydrolysis of the 17b esters (Fig. 4). It was assumed that this kind of mixed anhydride would be potentially toxic and probably cataractogenic, similar to the Hines rearrangement process. The 17a carbonates were a new class of corticosteroids, which are very difficult to make on the normal corticosteroid derivatives, but after the 21 carbon is oxidatively removed, the synthesis of the 17a carbonate is quite easy. A modification in the 17b position involved a variety of esters and many of them showed a different degree of activity, which at the early times was determined using the classical cotton pellet granuloma and human vasoconstrictor studies [21– 25]. It was found quite early that this position is quite sensitive to small modifications as this is an important pharmacophore and thus the freedom for changes is very restricted. For example, while chloromethyl or fluoromethyl esters showed very good activity, the activity was in order of magnitude reduced, if one additional methylene was introduced as the chloroethyl or a-chloroethylidene derivatives are very weak. Simple alkyl esters are also virtually inactive, thus the final selection involved a chloromethyl ester of various 17a-carbonates having substituents in different position of the steroid skeleton. A proprietary position was established by early patenting [26], and subsequently detailed studies
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Fig. 2. Major metabolic pathways of hydrocortisone.
determining therapeutic indices as the ratio between antiinflammatory and thymus involution activity was determined for a large number of derivatives. Some examples for the improvement in therapeutic index are shown on Table 1. It is noteworthy that the classical steroids, regardless of their intrinsic activity show similar therapeutic index. Thus hydrocortisone 17a-butyrate or betamethasone 17a-valerate, which differ in intrinsic activity, have therapeutic indices of around 1. Many of the soft analogs however, showed
dramatic improvement in the therapeutic index [27,28]. The intrinsic activity of the soft steroids is quite remarkable. Recent studies on binding to rat lung cytosolic corticosteroid receptors showed that a number of the compounds approach and exceed the binding affinity of the most potent corticosteroids known, as shown in Table 2. Selection of the derivatives for development was based on various properties. Of course, the most important property is the therapeutic index, but
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Fig. 3. Design, metabolism, and general structure of soft corticosteroids.
others considered were the availability, synthesis, and ‘softness’, that is, rate and ease of metabolic deactivation. One of the final selected class of compounds were the derivatives of D1 -cortienic acid, the inactive metabolite of prednisolone. The final selected derivative contains 17a-ethyl carbonate and 17b-chloromethyl ester. This compound shown in Fig. 5, is loteprednol etabonate, the drug which has recently received FDA approval.
Unlike for many other drugs, the route of development was technically easy, but due to financial problems, it did involve various companies. First, as mentioned, Otsuka Pharmaceutical Company was the sponsor (1980–1985, synthesis, preclinical studies, animal toxicology, and limited Phase I / II human studies aiming dermatological use). Xenon Vision Inc., was then established specifically to explore the potential ophthalmic use of the soft steroids (1986–
Fig. 4. Formation of mixed anhydrides.
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Table 1 Therapeutic indices of representative soft steroids as compared to reference steroids R1
R2
R3
X1
X2
D1
ED 50 a
CH 2 Cl
COOi–C 3 H 7
H
H
H
2
CH 2 Cl
COOi–C 3 H 7
H
H
H
1
CH 2 Cl
COOCH 3
a-CH 3
F
H
1
460 (360–623) 119 (60–202) 2.38 (1.60–3.78) 480 (313–892) 100
Hydrocortisone 17-butyrate Betamethasone 17-valerate
Rel. pot. 1 4 202 1 5
TED 40 b
Rel. pot.
TI c
31.0 (23.9–41.9) 16.2 (11.2–23.2) 46.0 (36.0–62.1) 1.3 (1.1–1.5) 0.3 (0.24–0.36)
1 / 24
24
1 / 12
48
1 / 36
7270
1
1
4
1
a
Anti-inflammatory activity in the cotton pellet granuloma test (mg / pellet). Thymus inhibition effect subcutaneously (mg / kg). c Therapeutic index: the ratio of the relative potency for the ED 50 to the relative potency (rel. pot.) for the TED 40 ; hydrocortisone 17-butyrate has been assigned arbitrarily a value of 1. b
1991). Regulatory animal toxicology, Phase I and Phase II human studies were conducted, establishing proof of concept in giant papillary conjunctivitis and allergic conjunctivitis. Finally, the involvement of Pharmos Corporation and Bausch and Lomb Inc. (1992–1996, Phase III studies in giant papillary
conjunctivitis, allergic conjunctivitis, uveitis, and post cataract surgery), led to submission of the NDAs in 1995 and 1996, respectively. Some of the important properties of loteprednol etabonate are shown on Table 3; LE has a therapeutic index of 24. More importantly, it did not effect
Table 2 Binding of soft glucocorticoids to the glucocorticoid receptor of rat lung No.
R1
R2
R3
X1
X2
RBAa
LE 5643 5649 5651 5654 5685 5602 5606 5608 5614 5613 5618 5621 5623 5660
CH 2 Cl CH 2 Cl CH 3 CH 2 OC 2 H 5 CH(CH 3 )Cl CH 2 CH 2 Cl CH 2 Cl CH 2 SCH 3 C2H5 C2H5 CH 3 CH 2 Cl CH 2 Cl (no O)CH 2 Cl CH 2 Cl, 11-keto
COOC 2 H 5 COOC 6 H 5 COOi–C 3 H 7 COOi–C 3 H 7 COOi–C 3 H 7 COOi–C 3 H 7 COOn–C 4 H 9 COOC 2 H 5 COOC 2 H 5 COOC 2 H 5 COOCH 2 Cl COOCH 2 OCH 3 COOCOOCH 3 COOCH 2 OCH 3 COOC 2 H 5
H H H H H H H H H H H H H H a-CH 3
H H H H H H H H H F H H H H F
H H H H H H H H H H H H H H H
320 80 3 ,1 10 1 110 3 ,1 ,1 0 16 0 10 16
H
R2
R3
X1
X2
,1
Acid metabolites are inactive: Hydrocortisone 17a-butyrate Dexamethasone Betamethasone 17a-valerate a
Relative binding affinity, RBA dexamethasone 5100.
55 100 820
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2.2. Chemical delivery systems
Fig. 5. Structure of loteprednol etabonate.
the intraocular pressure in rabbits [29], which was then confirmed in various human studies. At two concentrations, 0.5 and 0.2% the drug was compared in a number of randomized double masked placebo controlled studies, demonstrating good activity and dramatically reduced effect on the intraocular pressure. A number of these studies were already published [16–20] and others are going to be published. At this point, well over 2,000 patients were treated with LE, with great success. It is particularly important that treatment of postoperative inflammation, after removal of cataracts was successfully treated with LE, without the dreaded IOP side effects. The new products, LotemaxE and AlrexE reached the US market on June 1, 1998. Loteprednol etabonate, as a safe, soft steroid has many other potential uses. Based on animal studies [30,31], it is being developed for the treatment of colitis, various atopic dermatitis, and asthma.
Among the CDSs, the general brain targeting method using a dihydrotrigonelline↔trigonelline targetor system has found wide applicability. During the last decade, the system has been explored with a wide variety of drug classes – biogenic amines: phenylethylamine [32,33]; steroid hormones: testosterone [34], progestins [35], dexamethasone [36,37], progesterone [38], estradiol [39–43]; anti-infective agents: penicillins [44,45]; antivirals: acyclovir [46,47], trifluorothymidine [48,49], ribavirin [50,51], deoxyuridines [52], 29-F-5-methylarabinosyluracil [53]; antiretrovirals: zidovudine (AZT) [54–63], 29,39-dideoxythymidine [64], ganciclovir [65], cytosinyl-oxathiolane [66]; anticancer agents: lomustine (CCNU) [67,68], HECNU [68], chlorambucil [69]; neurotransmitters: dopamine [70–73], GABA [74,75]; nerve growth factor (NGF) inducers: catechol derivatives [76,77]; anticonvulsants: GABA [75], phenytoin [78], stiripentol [79], felodipine [80]; monoamine oxidase (MAO) inhibitors: tranylcypromine [81]; cholinesterase inhibitors: 9-aminotetrahydroacridine [82]; antioxidants: LY231617 [83]; nonsteroidal anti-inflammatory drugs (NSAIDs): indomethacin [84], naproxen [84]; anesthetics: propofol [85]; nucleosides: adenosine [86]; and peptides: tryptophan [87,88], Leu-enkephalin analogue [89,90], thyrotropin-releasing hormone (TRH) analogue [91], kyotorphine analogues [5,10,92]. Of particular interest is the most recent development and extension of the brain targeting system to neuropeptides applying the molecular packaging approach [5,10,89–92]. Delivering peptides such as enkephalin, TRH (thyrotropin releasing hormone), or
Table 3 Comparison of loteprednol etabonate with other steroids Treatment
N
ED 50 a
Rel. pot.
TED 50 b
Rel. pot.
TI c
Loteprednol etabonate (0.1%) Hydrocortisone 17-butyrate (0.1%) Betamethasone 17a-valerate (0.12%) Clobetasol 17a-propionate (0.1%)
8 8 8 8
178.0 121.0 84.8 2.9
0.48 0.70 1.00 29.70
10,000 369 212 11
0.02 0.57 1.00 19.30
24.0 1.3 1.0 1.5
a
Anti-inflammatory activity in the cotton pellet granuloma test (mg / pellet). Thymolysis potency (mg / pellet). c Therapeutic index: the ratio of the relative potency for the ED 50 to the relative potency (rel. pot.) for the TED 50 ; betamethasone 17a-valerate has been assigned arbitrarily a value of 1. b
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kyotorphin analogs is more complex because they can be rapidly inactivated by ubiquitous peptidases in the blood–brain barrier. Therefore, for a successful delivery, three issues have to be solved simultaneously: enhance passive transport by increasing the lipophilicity, assure enzymatic stability to prevent premature degradation, and exploit the ‘lock-in’ mechanism to provide targeting. The solution is a complex molecular packaging strategy, where the peptide unit is part of a bulky molecule, dominated by lipophilic modifying groups that direct blood– brain barrier penetration and prevent recognition by peptidases. Such a brain-targeted packaged peptide delivery system contains the following major components: the redox targetor (T); a spacer function (S), consisting of strategically used amino acids to ensure timely removal of the charged targetor from the peptide; the peptide itself (P); and a bulky lipophilic moiety (L) attached through an ester bond or sometimes through a C-terminal adjuster (A) at the carboxyl terminal to enhance lipid solubility and to disguise the peptide nature of the molecule. Because the importance of physicochemical (i.e. partition) properties during the sequential metabolism, knowing how these properties relate to molecular structure is of great interest. However, because these latest CDSs are quite large molecules and often contain peptide constituents, they are difficult to handle with most available computer methods, including semiempirical quantum chemical methods. Nevertheless, our recently developed, molecular sizebased method [93–95] allows us to estimate with excellent accuracy the partition and solubility properties of the potential lipophilic constructs and their predicted enzymatic intermediates and byproducts [4–6] making possible integration of some quantitative physicochemical aspects into future CDS designs. The model can estimate octanol / water partition properties for a wide variety of organic molecules including nonzwitterionic peptides and some large compounds where usual two-dimensional fragmental methods completely fail. The first successful delivery was achieved for an analogue of leucine–enkephalin, a naturally occurring linear pentapeptide (Tyr-Gly-Gly-Phe-Leu) that binds to opioid receptors [89]. These opioid peptides are best-known for their central analgesic effect, but they are also implicated in mediating neuroendocrine
activity, behavioral stress responses, eating disorders, alcoholism, schizophrenia, and in modulating memory function, heart rate, blood pressure, gastrointestinal function, sexual behavior and development. Fig. 6 shows the sequential metabolism of a brain targeting CDS during delivery of the leucine enkephalin analogue Tyr-D-Ala-Gly-Phe-D-Leu (DADLE). In rat brain tissue samples collected 15 min after intravenous CDS administration, electrospray ionization mass spectrometry clearly showed the presence of the locked in T 1 -D form at an estimated concentration of 600 pmol / g [89]. The same ion was absent from the sample collected from the control animals treated with the vehicle solution only. To optimize this delivery strategy, an effective synthetic route for peptide CDSs was established, and the role of the spacer and the lipophilic functions was investigated [90]. Intravenous injection of the four CDSs synthesized by a segment-coupling method produced a significant and long-lasting (more than 5 h) response in rats as measure by tail-flick latency tests. The efficacy of the CDSs could be influenced by modifying the spacer (S) and lipophilic (L) components, proving that they have important roles in determining molecular properties and timing of the metabolic sequence. The bulkier cholesteryl group used as L showed a better efficacy than the smaller 1-adamantaneethyl, but the most important factor for manipulating the rate of peptide release and the pharmacological activity turned out to be the S function: proline as spacer produced more potent analgesia than alanine. A similar strategy was used to deliver a thyrotropin-releasing hormone (TRH) analogue to the central nervous system [91]. These analogues are potential agents for treating neurodegenerative disorders such as Alzheimer’s disease. However, because the final peptide following delivery has no free –NH 2 and –COOH termini, a precursor sequence (Gln-Leu-Pro-Gly) that will ultimately produce the final TRH analog was packaged. This meant including two additional steps in the metabolic sequence: one where the C-terminal adjuster glycine is cleaved by peptidyl glycine a-amidating monooxygenase to form the ending prolinamide, and one where the N-terminal pyroglutamyl is formed from glutamine by glutaminyl cyclase. Selecting a suitable spacer was also important for the efficacy of TRH-CDSs as
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Fig. 6. The sequential metabolism employed the brain targeting of a Leu-enkephalin analogue (DADLE) by retrometabolic design.
measured by the decrease in the barbiturate-induced sleeping time in mice after i.v. injection. At equimolar doses (30 mmol / kg) the TRH analogue itself showed only a marginal decrease, while the CDS with L-Ala spacer produced about 30% reduction,
and the one with a double alanine spacer produced a greater than 50% decrease. Finally, we also successfully delivered a kyotorphin analogue (Tyr-Lys) that has activity similar to kyotorphin itself [5,10]. Kyotorphin is an endogen-
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ous neuropeptide (Tyr-Arg) that exhibits analgesic action through the release of enkephalin, and its analgesic activity is even larger than that of enkephalin. For this delivery system, from all the various spacers tried – proline, proline-alanine, and proline-proline spacers – the double proline compound was the most effective. It was found that even with the single proline spacer the corresponding CDS showed good activity on the rat tail-flick latency test. Activity was already significant at a 1 mg / kg dose and leveled off at about 7 mg / kg. This represents an improvement of about two orders of magnitude compared to the |200 mg / kg dose necessary to observe activity when the peptide itself is given intravenously. Since the analgesic effect of these CDSs could be reversed by naloxone, an opiate antagonist, central opiate receptors must be responsible for mediating the induced analgesia (Fig. 7). Several intermediates and building blocks were also
studied, but only administration of the whole molecular package produced significant pharmaceutical response, confirming that only the designed metabolic sequence as a whole is effective in delivering peptides across the blood–brain barrier. Molecular packaging of peptides is a rational drug design approach that achieved the first documented non-invasive brain delivery of these important biomolecules in pharmacologically significant amounts. Since it not only overcomes the obstacles imposed by the blood–brain barrier but exploits its special trafficking properties to provide a ‘lock-in’ mechanism for a sustained release, this approach may represent an important step toward future generations of high efficiency neuropharmaceuticals obtained from biologically active peptides. After it was first published [89], it was included in the Harvard Health Letters [96] as one of the ten most important discoveries of 1992.
Fig. 7. Reversal of the analgesia produced by YK-(PP)CDS by naloxone.
N. Bodor / Journal of Controlled Release 62 (1999) 209 – 222
Acknowledgements I am indebted to many of my former and current coworkers, without whom none of these accomplishments could have been achieved. For the success of Loteprednol etabonate, special thanks are due to A. Otsuka, A. Sonoda, S. Tamada, M. Honma, M. Kato, T. Morita, Y. Irie, and K. Tomita of Otsuka Pharmaceutical Co., J. Howes, K. Lawson and P. Druzgala of Xenon Vision Inc., J. Howes, E. Pop, M. Brewster of Pharmos and E.R. Strahlman of Bausch and Lomb Co., as well as, T. Loftsson, W.-M. Wu, G. Hochhaus from the University of Florida. For the brain-targeting of peptides, the contribution of H. Farag, M. Kawamura, L. Prokai, K. Tatrai-Prokai, W.-M. Wu, P. Chen, X. Ouyang and P. Buchwald is gratefully acknowledged.
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[68] K. Raghavan, T. Loftsson, M.E. Brewster, N. Bodor, Improved delivery through biological membranes. XLV. Synthesis, physical-chemical evaluation, and brain uptake studies of 2-chloroethyl nitrosourea delivery system, Pharm. Res. 9 (1992) 743–749. [69] N. Bodor, V. Venkatraghavan, D. Winwood, K. Estes, M.E. Brewster, Improved delivery through biological membranes. XLI. Brain-enhanced delivery of chlorambucil, Int. J. Pharm. 53 (1989) 195–208. [70] N. Bodor, J.W. Simpkins, Redox delivery system for brainspecific, sustained release of dopamine, Science 221 (1983) 65–67. [71] N. Bodor, H.H. Farag, Improved delivery through biological membranes. 13, Brain-specific delivery of dopamine with a dihydropyridine-pyridinium salt type redox delivery system. J. Med. Chem. 26 (1983) 528–534. [72] F.A. Omar, H.H. Farag, N. Bodor, Synthesis and evaluation of a redox chemical delivery system for brain-enhanced dopamine containing an activated carbamate-type ester, J. Drug Target. 2 (1994) 309–316. [73] V. Carelli, F. Liberatore, L. Scipione, M. Impicciatore, E. Barocelli, M. Cardellini, G. Giorgioni, New systems for the specific delivery and sustained release of dopamine to the brain, J. Control. Release 42 (1996) 209–216. [74] W.R. Anderson, J.W. Simpkins, P.A. Woodard, D. Winwood, W.C. Stern, N. Bodor, Anxiolytic activity of a brain delivery system for GABA, Psychopharmacology 92 (1987) 157– 163. [75] P.A. Woodard, D. Winwood, M.E. Brewster, K.S. Estes, N. Bodor, Improved delivery through biological membranes. XXI. Brain-targeted anti-convulsive agents, Drug Des. Deliv. 6 (1990) 15–28. [76] A. Kourounakis, N. Bodor, J. Simpkins, Synthesis and evaluation of a brain-targeted catechol derivative as a potential NGF-inducer, Int. J. Pharm. 141 (1996) 239–250. [77] A. Kourounakis, N. Bodor, J. Simpkins, Synthesis and evaluation of a brain-targeted chemical delivery system for the neurotrophomodulator 4-methylcatechol, J. Pharm. Pharmacol. 49 (1997) 1–9. [78] E. Shek, T. Murakami, C. Nath, E. Pop, N.S. Bodor, Improved anticonvulsant activity of phenytoin by a redox brain delivery system. III. Brain uptake and pharmacological effects, J. Pharm. Sci. 78 (1989) 837–843. [79] A.V. Boddy, K. Zhang, F. Lepage, F. Tombret, J.G. Slatter, T.A. Baillie, R.H. Levy, In vitro and in vivo investigations of dihydropyridine-based chemical delivery systems for anticonvulsants, Pharm. Res. 8 (1991) 690–697. [80] S.H. Yiu, E.E. Knaus, Synthesis, biological evaluation, calcium channel antagonist activity, and anticonvulsant activity of felodipine coupled to a dihydropyridine– pyridinium salt redox chemical delivery system, J. Med. Chem. 39 (1996) 4576–4582. ´ ´ [81] K. Prokai-Tatrai, E. Pop, W. Anderson, J.-L. Lin, M.E. Brewster, N. Bodor, Redox derivatives of tranylcypromine: synthesis, properties, and monoamine oxidase inhibitor activity of some chemical delivery systems, J. Pharm. Sci. 80 (1991) 255–261. ´ ´ [82] E. Pop, K. Prokai-Tatrai, J.D. Scott, M.E. Brewster, N.
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da, M. Kawamura, J. Simpkins, A strategy for delivering peptides into the central nervous system by sequential metabolism, Science 257 (1992) 1698–1700. K. Prokai-Tatrai, L. Prokai, N. Bodor, Brain-targeted delivery of a leucine-enkephalin analogue by retrometabolic design, J. Med. Chem. 39 (1996) 4775–4782. L. Prokai, X.-D. Ouyang, W.-M. Wu, N. Bodor, Chemical delivery system to transport a pyroglutamyl peptide to the central nervous system, J. Am. Chem. Soc. 116 (1994) 2643–2644. N. Bodor, P. Chen, W.-M. Wu, L. Prokai, Brain targeting of basic amino acids and their redox analogs containing peptides, in: 2nd World Meeting on Pharmaceutics, Biopharmaceutics, Pharmaceutical Technology, Paris, May 25– 28, CNIT, 1998. N. Bodor, P. Buchwald, Molecular size based approach to estimate partition properties for organic solutes, J. Phys. Chem. B 101 (1997) 3404–3412. P. Buchwald, N. Bodor, Octanol–water partition of nonzwitterionic peptides: Predictive power of a molecular size based model, Proteins 30 (1998) 86–99. P. Buchwald, N. Bodor, Molecular size-based model to describe simple organic liquids, J. Phys. Chem. B 102 (1998) 5715–5726. Harvard Health Letter 18 (5) (1993).
Recent advances in retrometabolic design approaches N. Bodor* Center for Drug Discovery, University of Florida, P.O. Box 100497, JHMHC, Gainesville, FL 32610, USA
Abstract The retrometabolic drug design approaches simultaneously incorporate structure activity (SAR) and structure metabolism (SMR) relationships in the design process. Two major approaches were developed, the chemical delivery systems (CDS), which allow chemical–enzymatic targeting of drugs via strategic sequential enzymatic activation of the inactive CDSs. On the opposite end of the retrometabolic design loop are the soft drugs (SD), which are designed to have highly improved therapeutic indeces by controlling their metabolism, after they achieve their therapeutic role. One of the most successful SD class is the ‘inactive metabolite approach’, where the design starts from an inactive metabolite of a drug. Its strategic manipulation yields an isosteric / isoelectronic drug analog, which is enzymatically deactivated to the very inactive metabolite at the desired compartment and with controlled rate. Overall, retrometabolic approaches represent a complex collection of chemical–enzymatic means for the design of safer drugs and for their controlled release. Most recent advances involve FDA approval of a soft steroid, as well as the first successful brain targeting of various neuropeptides and their brain-targeted analogs. 1999 Elsevier Science B.V. All rights reserved. Keywords: Drug design; Retrometabolic methods; Brain targeting; Redox targetor systems; Therapeutic index; Sequential metabolism
1. Introduction A very large number of promising drug candidates have failed to become drugs, due to the various toxic side effects they exhibit. The activity and toxicity aspects of a drug candidate are the major issues evaluated during the drug development process. These two major properties, the efficiency and safety, however, are generally studied separately, as the first aim of drug design is always the activity. But it is well-known that essentially the ratio between the activity and toxicity, that is, the therapeutic index is the most important property of a drug. In order to design active, safer drugs, one should *Tel.: 11-352-3928186; fax: 11-352-3928589. E-mail address: [email protected] (N. Bodor)
include structure metabolism relationships (SMR) (the safety aspect can very well be affected by metabolism) in addition to the structure activity (SAR) relationships. The combination of these two relationships, represent the retrometabolic drug design (RMDD) concepts. The general principles of retrometabolic drug design approaches, have been reviewed recently in various publications [1–6], and a biannual international conference [7] addresses the major developments in the field. Thus, here only a brief summary is given. The retrometabolic drug design approaches include two distinct methods to improve the therapeutic index of a drug (D). One, is the general concept of the chemical delivery system (CDS), which is defined as a biologically inert molecule containing the drug (D) in an appropriately modified form, that
0168-3659 / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0168-3659( 99 )00040-1
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requires several (mostly enzymatic) steps during its conversion to the active drug, and that enhances drug targeting to a particular organ or site. Within this design process, the drug is chemically converted to an inactive precursor, which contains two types of attachments, the most important is the targetor (T), while modifier functions (F 1 ... F n ) will be used if necessary to optimize the chemical–physical properties of the molecule to achieve better delivery. Targeting is achieved by design: the CDS will undergo sequential metabolic conversions removing the modifiers and finally the targetor after this moiety fulfills its site or organ targeting role. In general, these methods represent true targeting and controlled drug release. The targeting and sustained release properties are controlled by design, based on various enzymatic systems present, either in the whole body or in specific sites. In general, various enzyme systems are involved, such as oxidative, reductive or hydrolytic enzymes. Examples are abundant in the literature, including brain targeting and controlled release of drugs and neuropeptides, targeting various drugs to the anterior segment of the eye, targeting to lungs and others [2,4,8–10]. The CDS approach is summarized in a simple form by the left hand side of the retrometabolic drug design loop shown on Fig. 1.
The other, opposite but equally successful approach in retrometabolic design, involves the soft drugs, as simplistically represented by the right-hand side of the loop [4,11,12]. As illustrated here drugs undergo multiple metabolism, including conversion to analog metabolites (D 1 ... D m ) having similar type of activity as D, different other metabolites (M 1 ... M k ) and reactive intermediates (I 1* ... I *n ), among which there are inactive metabolite(s) (M i ). One of the most important approaches in the soft drug design involves the ‘inactive metabolite approach’, whereby the design starts with an inactive metabolite of an active drug, followed by converting this inactive metabolite to an isosteric / isoelectronic analog of the lead drug (soft drug, SD), assuring thus, activity. The design of this soft analog (SD) is however done in such a way that the SD will metabolize in one-step back to the very inactive metabolite the design started with, without undergoing any other metabolism. This process happens after the drug achieves its therapeutic role at the site of action, and thus prevents the rest of the body to be exposed to the active drug or to various active or reactive metabolic products. One can see that the two approaches, essentially are opposite of each other, the CDS are inactive by
Fig. 1. The retrometabolic drug design (RMDD) loop.
N. Bodor / Journal of Controlled Release 62 (1999) 209 – 222
design, and activated strategically at the site of action, while the SDs are active, novel drugs which exert their desired activity at the applied site, however, they will be destroyed metabolically in a timely fashion, so they cannot effect the other sites in the body. One other difference, between the two approaches, is the type of enzymes generally involved in the strategic activation or the activation, respectively. While in the case of CDSs, various enzymes, including oxidative and reductive enzymes are also involved, in the design of soft drugs, the objective is to use preferentially hydrolytic enzymes, and to avoid oxidative processes.
2. Results and discussion
2.1. Loteprednol etabonate It would be informative to review a successful case of design of a new, important soft drug. This is prompted by the fact that loteprednol etabonate (LE), a soft steroid [13–20], has received on March 9, 1998, FDA approval as the active ingredient of two ophthalmic preparations, LotemaxE and AlrexE. Approval for the two products was received simultaneously, and in this way loteprednol became the only corticosteroid receiving FDA approval for all inflammatory and allergy related ophthalmic disorders, including post-surgical inflammation, uveitis, allergic conjunctivitis, giant papillary conjunctivitis (GPC), etc. As a start, it should be mentioned that corticosteroids, although the most important drugs to treat ocular inflammations and allergies, are contraindicated, as in addition to the general systemic and local corticosteroid side effects, in the eye, they also produce elevation of the intraocular pressure (IOP), that is, they cause glaucoma, in addition to provoking cataract. Thus, it was of utmost importance to design an active corticosteroid which is void of these serious side effects. Fig. 2 illustrates the major metabolic pathways of hydrocortisone, the simplest (natural) corticosteroid. The acidic metabolites are inactive, among which, cortienic acid, where the oxidation removed the 21 carbon atom, is one of the major metabolites excreted in the urine of man. This inactive metabolite was used as the starting point to produce various soft
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analogs by esterifying the cortienic acid in the 17b position, as well as, to introduce necessary lipophilic functions in the 17a position. Further modifications are common in the corticosteroid design, involving D1 double bond, halogen in 9a and / or 6a positions, and methyl or hydroxy groups in 16a or 16b positions. The changes critical to the soft drug design, thus are the modifications in the 17b and 17a positions. The general structure of the designed soft corticosteroid classes, the design process and metabolism are summarized in Fig. 3.
2.1.1. A brief history The first soft steroids of this kind were synthesized in the late 1970s followed by a systematic synthetic study performed in collaboration with Otsuka Pharmaceutical Company in 1980–1981. From the beginning our approach was concentrating on using 17a carbonates, instead of 17a esters, in order to assure enhanced stability and thus prevent mixed anhydride formation from 17a esters following hydrolysis of the 17b esters (Fig. 4). It was assumed that this kind of mixed anhydride would be potentially toxic and probably cataractogenic, similar to the Hines rearrangement process. The 17a carbonates were a new class of corticosteroids, which are very difficult to make on the normal corticosteroid derivatives, but after the 21 carbon is oxidatively removed, the synthesis of the 17a carbonate is quite easy. A modification in the 17b position involved a variety of esters and many of them showed a different degree of activity, which at the early times was determined using the classical cotton pellet granuloma and human vasoconstrictor studies [21– 25]. It was found quite early that this position is quite sensitive to small modifications as this is an important pharmacophore and thus the freedom for changes is very restricted. For example, while chloromethyl or fluoromethyl esters showed very good activity, the activity was in order of magnitude reduced, if one additional methylene was introduced as the chloroethyl or a-chloroethylidene derivatives are very weak. Simple alkyl esters are also virtually inactive, thus the final selection involved a chloromethyl ester of various 17a-carbonates having substituents in different position of the steroid skeleton. A proprietary position was established by early patenting [26], and subsequently detailed studies
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Fig. 2. Major metabolic pathways of hydrocortisone.
determining therapeutic indices as the ratio between antiinflammatory and thymus involution activity was determined for a large number of derivatives. Some examples for the improvement in therapeutic index are shown on Table 1. It is noteworthy that the classical steroids, regardless of their intrinsic activity show similar therapeutic index. Thus hydrocortisone 17a-butyrate or betamethasone 17a-valerate, which differ in intrinsic activity, have therapeutic indices of around 1. Many of the soft analogs however, showed
dramatic improvement in the therapeutic index [27,28]. The intrinsic activity of the soft steroids is quite remarkable. Recent studies on binding to rat lung cytosolic corticosteroid receptors showed that a number of the compounds approach and exceed the binding affinity of the most potent corticosteroids known, as shown in Table 2. Selection of the derivatives for development was based on various properties. Of course, the most important property is the therapeutic index, but
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213
Fig. 3. Design, metabolism, and general structure of soft corticosteroids.
others considered were the availability, synthesis, and ‘softness’, that is, rate and ease of metabolic deactivation. One of the final selected class of compounds were the derivatives of D1 -cortienic acid, the inactive metabolite of prednisolone. The final selected derivative contains 17a-ethyl carbonate and 17b-chloromethyl ester. This compound shown in Fig. 5, is loteprednol etabonate, the drug which has recently received FDA approval.
Unlike for many other drugs, the route of development was technically easy, but due to financial problems, it did involve various companies. First, as mentioned, Otsuka Pharmaceutical Company was the sponsor (1980–1985, synthesis, preclinical studies, animal toxicology, and limited Phase I / II human studies aiming dermatological use). Xenon Vision Inc., was then established specifically to explore the potential ophthalmic use of the soft steroids (1986–
Fig. 4. Formation of mixed anhydrides.
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Table 1 Therapeutic indices of representative soft steroids as compared to reference steroids R1
R2
R3
X1
X2
D1
ED 50 a
CH 2 Cl
COOi–C 3 H 7
H
H
H
2
CH 2 Cl
COOi–C 3 H 7
H
H
H
1
CH 2 Cl
COOCH 3
a-CH 3
F
H
1
460 (360–623) 119 (60–202) 2.38 (1.60–3.78) 480 (313–892) 100
Hydrocortisone 17-butyrate Betamethasone 17-valerate
Rel. pot. 1 4 202 1 5
TED 40 b
Rel. pot.
TI c
31.0 (23.9–41.9) 16.2 (11.2–23.2) 46.0 (36.0–62.1) 1.3 (1.1–1.5) 0.3 (0.24–0.36)
1 / 24
24
1 / 12
48
1 / 36
7270
1
1
4
1
a
Anti-inflammatory activity in the cotton pellet granuloma test (mg / pellet). Thymus inhibition effect subcutaneously (mg / kg). c Therapeutic index: the ratio of the relative potency for the ED 50 to the relative potency (rel. pot.) for the TED 40 ; hydrocortisone 17-butyrate has been assigned arbitrarily a value of 1. b
1991). Regulatory animal toxicology, Phase I and Phase II human studies were conducted, establishing proof of concept in giant papillary conjunctivitis and allergic conjunctivitis. Finally, the involvement of Pharmos Corporation and Bausch and Lomb Inc. (1992–1996, Phase III studies in giant papillary
conjunctivitis, allergic conjunctivitis, uveitis, and post cataract surgery), led to submission of the NDAs in 1995 and 1996, respectively. Some of the important properties of loteprednol etabonate are shown on Table 3; LE has a therapeutic index of 24. More importantly, it did not effect
Table 2 Binding of soft glucocorticoids to the glucocorticoid receptor of rat lung No.
R1
R2
R3
X1
X2
RBAa
LE 5643 5649 5651 5654 5685 5602 5606 5608 5614 5613 5618 5621 5623 5660
CH 2 Cl CH 2 Cl CH 3 CH 2 OC 2 H 5 CH(CH 3 )Cl CH 2 CH 2 Cl CH 2 Cl CH 2 SCH 3 C2H5 C2H5 CH 3 CH 2 Cl CH 2 Cl (no O)CH 2 Cl CH 2 Cl, 11-keto
COOC 2 H 5 COOC 6 H 5 COOi–C 3 H 7 COOi–C 3 H 7 COOi–C 3 H 7 COOi–C 3 H 7 COOn–C 4 H 9 COOC 2 H 5 COOC 2 H 5 COOC 2 H 5 COOCH 2 Cl COOCH 2 OCH 3 COOCOOCH 3 COOCH 2 OCH 3 COOC 2 H 5
H H H H H H H H H H H H H H a-CH 3
H H H H H H H H H F H H H H F
H H H H H H H H H H H H H H H
320 80 3 ,1 10 1 110 3 ,1 ,1 0 16 0 10 16
H
R2
R3
X1
X2
,1
Acid metabolites are inactive: Hydrocortisone 17a-butyrate Dexamethasone Betamethasone 17a-valerate a
Relative binding affinity, RBA dexamethasone 5100.
55 100 820
N. Bodor / Journal of Controlled Release 62 (1999) 209 – 222
215
2.2. Chemical delivery systems
Fig. 5. Structure of loteprednol etabonate.
the intraocular pressure in rabbits [29], which was then confirmed in various human studies. At two concentrations, 0.5 and 0.2% the drug was compared in a number of randomized double masked placebo controlled studies, demonstrating good activity and dramatically reduced effect on the intraocular pressure. A number of these studies were already published [16–20] and others are going to be published. At this point, well over 2,000 patients were treated with LE, with great success. It is particularly important that treatment of postoperative inflammation, after removal of cataracts was successfully treated with LE, without the dreaded IOP side effects. The new products, LotemaxE and AlrexE reached the US market on June 1, 1998. Loteprednol etabonate, as a safe, soft steroid has many other potential uses. Based on animal studies [30,31], it is being developed for the treatment of colitis, various atopic dermatitis, and asthma.
Among the CDSs, the general brain targeting method using a dihydrotrigonelline↔trigonelline targetor system has found wide applicability. During the last decade, the system has been explored with a wide variety of drug classes – biogenic amines: phenylethylamine [32,33]; steroid hormones: testosterone [34], progestins [35], dexamethasone [36,37], progesterone [38], estradiol [39–43]; anti-infective agents: penicillins [44,45]; antivirals: acyclovir [46,47], trifluorothymidine [48,49], ribavirin [50,51], deoxyuridines [52], 29-F-5-methylarabinosyluracil [53]; antiretrovirals: zidovudine (AZT) [54–63], 29,39-dideoxythymidine [64], ganciclovir [65], cytosinyl-oxathiolane [66]; anticancer agents: lomustine (CCNU) [67,68], HECNU [68], chlorambucil [69]; neurotransmitters: dopamine [70–73], GABA [74,75]; nerve growth factor (NGF) inducers: catechol derivatives [76,77]; anticonvulsants: GABA [75], phenytoin [78], stiripentol [79], felodipine [80]; monoamine oxidase (MAO) inhibitors: tranylcypromine [81]; cholinesterase inhibitors: 9-aminotetrahydroacridine [82]; antioxidants: LY231617 [83]; nonsteroidal anti-inflammatory drugs (NSAIDs): indomethacin [84], naproxen [84]; anesthetics: propofol [85]; nucleosides: adenosine [86]; and peptides: tryptophan [87,88], Leu-enkephalin analogue [89,90], thyrotropin-releasing hormone (TRH) analogue [91], kyotorphine analogues [5,10,92]. Of particular interest is the most recent development and extension of the brain targeting system to neuropeptides applying the molecular packaging approach [5,10,89–92]. Delivering peptides such as enkephalin, TRH (thyrotropin releasing hormone), or
Table 3 Comparison of loteprednol etabonate with other steroids Treatment
N
ED 50 a
Rel. pot.
TED 50 b
Rel. pot.
TI c
Loteprednol etabonate (0.1%) Hydrocortisone 17-butyrate (0.1%) Betamethasone 17a-valerate (0.12%) Clobetasol 17a-propionate (0.1%)
8 8 8 8
178.0 121.0 84.8 2.9
0.48 0.70 1.00 29.70
10,000 369 212 11
0.02 0.57 1.00 19.30
24.0 1.3 1.0 1.5
a
Anti-inflammatory activity in the cotton pellet granuloma test (mg / pellet). Thymolysis potency (mg / pellet). c Therapeutic index: the ratio of the relative potency for the ED 50 to the relative potency (rel. pot.) for the TED 50 ; betamethasone 17a-valerate has been assigned arbitrarily a value of 1. b
216
N. Bodor / Journal of Controlled Release 62 (1999) 209 – 222
kyotorphin analogs is more complex because they can be rapidly inactivated by ubiquitous peptidases in the blood–brain barrier. Therefore, for a successful delivery, three issues have to be solved simultaneously: enhance passive transport by increasing the lipophilicity, assure enzymatic stability to prevent premature degradation, and exploit the ‘lock-in’ mechanism to provide targeting. The solution is a complex molecular packaging strategy, where the peptide unit is part of a bulky molecule, dominated by lipophilic modifying groups that direct blood– brain barrier penetration and prevent recognition by peptidases. Such a brain-targeted packaged peptide delivery system contains the following major components: the redox targetor (T); a spacer function (S), consisting of strategically used amino acids to ensure timely removal of the charged targetor from the peptide; the peptide itself (P); and a bulky lipophilic moiety (L) attached through an ester bond or sometimes through a C-terminal adjuster (A) at the carboxyl terminal to enhance lipid solubility and to disguise the peptide nature of the molecule. Because the importance of physicochemical (i.e. partition) properties during the sequential metabolism, knowing how these properties relate to molecular structure is of great interest. However, because these latest CDSs are quite large molecules and often contain peptide constituents, they are difficult to handle with most available computer methods, including semiempirical quantum chemical methods. Nevertheless, our recently developed, molecular sizebased method [93–95] allows us to estimate with excellent accuracy the partition and solubility properties of the potential lipophilic constructs and their predicted enzymatic intermediates and byproducts [4–6] making possible integration of some quantitative physicochemical aspects into future CDS designs. The model can estimate octanol / water partition properties for a wide variety of organic molecules including nonzwitterionic peptides and some large compounds where usual two-dimensional fragmental methods completely fail. The first successful delivery was achieved for an analogue of leucine–enkephalin, a naturally occurring linear pentapeptide (Tyr-Gly-Gly-Phe-Leu) that binds to opioid receptors [89]. These opioid peptides are best-known for their central analgesic effect, but they are also implicated in mediating neuroendocrine
activity, behavioral stress responses, eating disorders, alcoholism, schizophrenia, and in modulating memory function, heart rate, blood pressure, gastrointestinal function, sexual behavior and development. Fig. 6 shows the sequential metabolism of a brain targeting CDS during delivery of the leucine enkephalin analogue Tyr-D-Ala-Gly-Phe-D-Leu (DADLE). In rat brain tissue samples collected 15 min after intravenous CDS administration, electrospray ionization mass spectrometry clearly showed the presence of the locked in T 1 -D form at an estimated concentration of 600 pmol / g [89]. The same ion was absent from the sample collected from the control animals treated with the vehicle solution only. To optimize this delivery strategy, an effective synthetic route for peptide CDSs was established, and the role of the spacer and the lipophilic functions was investigated [90]. Intravenous injection of the four CDSs synthesized by a segment-coupling method produced a significant and long-lasting (more than 5 h) response in rats as measure by tail-flick latency tests. The efficacy of the CDSs could be influenced by modifying the spacer (S) and lipophilic (L) components, proving that they have important roles in determining molecular properties and timing of the metabolic sequence. The bulkier cholesteryl group used as L showed a better efficacy than the smaller 1-adamantaneethyl, but the most important factor for manipulating the rate of peptide release and the pharmacological activity turned out to be the S function: proline as spacer produced more potent analgesia than alanine. A similar strategy was used to deliver a thyrotropin-releasing hormone (TRH) analogue to the central nervous system [91]. These analogues are potential agents for treating neurodegenerative disorders such as Alzheimer’s disease. However, because the final peptide following delivery has no free –NH 2 and –COOH termini, a precursor sequence (Gln-Leu-Pro-Gly) that will ultimately produce the final TRH analog was packaged. This meant including two additional steps in the metabolic sequence: one where the C-terminal adjuster glycine is cleaved by peptidyl glycine a-amidating monooxygenase to form the ending prolinamide, and one where the N-terminal pyroglutamyl is formed from glutamine by glutaminyl cyclase. Selecting a suitable spacer was also important for the efficacy of TRH-CDSs as
N. Bodor / Journal of Controlled Release 62 (1999) 209 – 222
217
Fig. 6. The sequential metabolism employed the brain targeting of a Leu-enkephalin analogue (DADLE) by retrometabolic design.
measured by the decrease in the barbiturate-induced sleeping time in mice after i.v. injection. At equimolar doses (30 mmol / kg) the TRH analogue itself showed only a marginal decrease, while the CDS with L-Ala spacer produced about 30% reduction,
and the one with a double alanine spacer produced a greater than 50% decrease. Finally, we also successfully delivered a kyotorphin analogue (Tyr-Lys) that has activity similar to kyotorphin itself [5,10]. Kyotorphin is an endogen-
218
N. Bodor / Journal of Controlled Release 62 (1999) 209 – 222
ous neuropeptide (Tyr-Arg) that exhibits analgesic action through the release of enkephalin, and its analgesic activity is even larger than that of enkephalin. For this delivery system, from all the various spacers tried – proline, proline-alanine, and proline-proline spacers – the double proline compound was the most effective. It was found that even with the single proline spacer the corresponding CDS showed good activity on the rat tail-flick latency test. Activity was already significant at a 1 mg / kg dose and leveled off at about 7 mg / kg. This represents an improvement of about two orders of magnitude compared to the |200 mg / kg dose necessary to observe activity when the peptide itself is given intravenously. Since the analgesic effect of these CDSs could be reversed by naloxone, an opiate antagonist, central opiate receptors must be responsible for mediating the induced analgesia (Fig. 7). Several intermediates and building blocks were also
studied, but only administration of the whole molecular package produced significant pharmaceutical response, confirming that only the designed metabolic sequence as a whole is effective in delivering peptides across the blood–brain barrier. Molecular packaging of peptides is a rational drug design approach that achieved the first documented non-invasive brain delivery of these important biomolecules in pharmacologically significant amounts. Since it not only overcomes the obstacles imposed by the blood–brain barrier but exploits its special trafficking properties to provide a ‘lock-in’ mechanism for a sustained release, this approach may represent an important step toward future generations of high efficiency neuropharmaceuticals obtained from biologically active peptides. After it was first published [89], it was included in the Harvard Health Letters [96] as one of the ten most important discoveries of 1992.
Fig. 7. Reversal of the analgesia produced by YK-(PP)CDS by naloxone.
N. Bodor / Journal of Controlled Release 62 (1999) 209 – 222
Acknowledgements I am indebted to many of my former and current coworkers, without whom none of these accomplishments could have been achieved. For the success of Loteprednol etabonate, special thanks are due to A. Otsuka, A. Sonoda, S. Tamada, M. Honma, M. Kato, T. Morita, Y. Irie, and K. Tomita of Otsuka Pharmaceutical Co., J. Howes, K. Lawson and P. Druzgala of Xenon Vision Inc., J. Howes, E. Pop, M. Brewster of Pharmos and E.R. Strahlman of Bausch and Lomb Co., as well as, T. Loftsson, W.-M. Wu, G. Hochhaus from the University of Florida. For the brain-targeting of peptides, the contribution of H. Farag, M. Kawamura, L. Prokai, K. Tatrai-Prokai, W.-M. Wu, P. Chen, X. Ouyang and P. Buchwald is gratefully acknowledged.
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