Renin Inhibitors

Renin Inhibitors Colin M. Tice Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, USA Contents 1. Introduction 2. Biology 2.1. The renin–angiotensin system 2.2. Renin 2.3. Drugs targeting the RAS 2.4. Biomarkers and animal models 3. Classical renin inhibitors 4. Aliskiren 4.1. Aliskiren discovery 4.2. In vivo studies with aliskiren 5. Piperidines 6. Piperazines 7. Aminopyrimidines 8. Conclusion References

155 156 156 156 157 157 158 158 158 160 161 162 163 164 164

1. INTRODUCTION Hypertension is defined as systolic blood pressure of 4140 mmHg or diastolic blood pressure of 490 mmHg. It affects about 25% of most populations and the prevalence is much higher in older people [1]. Hypertension occurs more frequently in patients suffering from insulin resistance, high LDL cholesterol, high triglycerides and obesity, and it is considered to be one facet of metabolic syndrome. Hypertension is also a risk factor for cardiovascular disease, including myocardial infarction, stroke and heart failure, and for renal disease [2–5]. Drugs available for the treatment of hypertension include diuretics, b-blockers, aldosterone receptor antagonists, angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) alone and in combination. Nonetheless, hypertension is poorly controlled in many patients and the drugs prescribed may produce significant side effects. Renin has been recognized as a desirable target for antihypertensive drugs for almost four decades. Intensive efforts at many pharmaceutical companies in the 1980s, which led to the discovery of many potent inhibitors, have been reviewed [6–9]; however, no drug has reached the market. Over the past decade, new classes of renin inhibitors have been discovered and are progressing to market.

ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOLUME 41 ISSN: 0065-7743 DOI 10.1016/S0065-7743(06)41009-5

r 2006 Elsevier Inc. All rights reserved

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2. BIOLOGY 2.1. The renin–angiotensin system In the classical rennin–angiotensin system (RAS), renin is synthesized in juxtoglomerular cells of the kidney in response to various signals and is secreted into the blood. Renin cleaves the protein angiotensinogen, produced primarily in the liver, liberating the physiologically inert decapeptide angiotensin I (Ang I). Ang I is further cleaved by ACE to the octapeptide angiotensin II (Ang II), which activates the Ang II type 1 receptor (AT1). One of the downstream effects of AT1 activation is a rise in blood pressure [10]. Further investigations of the RAS in recent years have uncovered greater complexity in the system. Ang II is subject to cleavage by a variety of peptidases to afford shorter peptides, which are also pharmacologically active. Furthermore, additional angiotensin receptors, AT2, AT3 and AT4, which mediate different responses have been characterized. Ang II activates AT2, and possibly AT4, in addition to AT1. Ang IV (the 3–8 peptide) activates AT4. Evidence has also emerged for the presence of functioning local RASs in various tissues, including the heart [11–13]. Blocking these tissue RASs may be important in end-organ protection. P4

P3 P2 P1

P1' P2' P3' P4'

Angiotensinogen Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu--Val-Ile-His-Asn-glycoprotein Renin Ang I

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-OH ACE

Ang II

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-OH

2.2. Renin Renin [14] (EC 3.4.23.15) is a 44-kDa, 335-amino acid, glycosylated, monomeric aspartic protease. Renin is a member of the pepsin-like family [15]. Other members of this group include b-secretases 1 and 2, and cathepsins D and E. The renin gene is located on chromosome 1q32, spanning 12.5 kb of genomic DNA, and containing 10 exons and 9 introns. A number of SNPs have been identified but only one, in exon 9, yields an amino acid change (V351I). Two reports suggest an association between renin haplotype and essential hypertension [16,17]. The renin gene is translated into preprorenin, a protein with 401 amino acids. In the endoplasmic reticulum a 20-amino-acid signal peptide is cleaved to give prorenin, which is further processed by removal of an additional 46-amino-acid peptide in the Golgi apparatus to give renin itself [18].

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Renin is a highly specific enzyme with no characterized activity other than cleavage of angiotensinogen to produce Ang I. Recently, one group has described a renin receptor but its physiological role is unknown [18,19]. Cathepsin D and tonin can also cleave angiotensinogen to Ang I; however, under normal conditions this activity is not pharmacologically relevant [20]. PDB contains two apo X-ray structures [21,22] of human renin (1bbs, 2ren) and four liganded structures [23–25] of human renin (1hrn, 1rne, 1bim, 1bil). Structure 1hrn has the best resolution at 1.8 A˚.These structures reveal a binding site that interacts with residues P4 to P40 of angiotensinogen. Several of these structures show two conformations of the protein, termed open and closed, which differ mainly in the flap region (residues 72–81). Residues in the flap region form contacts with the P3, P2, P1 and P10 side chains of angiotensinogen [21]. Several additional X-ray structures of renin with bound inhibitors have also been described in the literature, but the coordinates are not publicly available [26–30].

2.3. Drugs targeting the RAS Two prominent classes of antihypertensive drugs, the ACE inhibitors, e.g. benazepril, and the ARBs, e.g. valsartan, function by blocking the RAS. Despite the demonstrated efficacy of these drugs in controlling hypertension and reducing endorgan damage, both mechanisms of action have some disadvantages [10]. Complete inhibition of ACE does not prevent the conversion of Ang I to Ang II by other peptidases, including chymase. Indeed, in cardiac tissue, most Ang II is produced by enzymes other than ACE. In contrast, inhibition of bradykinin cleavage by ACE causes the side effects of coughing and angioedema in a substantial number of patients. Although the ARBs prevent binding of Ang II to AT1, high levels of Ang II and its cleavage products remain in circulation and are available to activate AT2, AT3 and AT4. Renin is anticipated to be a superior target for antihypertensives [31,32].

2.4. Biomarkers and animal models In vivo studies of renin inhibitors have typically measured plasma renin activity and levels of Ang I and Ang II. Levels of all three components of the RAS should be reduced in a dose-dependent manner by an effective renin inhibitor. Significant differences exist in the sequences and specificity of human and most non-primate renins and angiotensinogens. Human renin inhibitors are generally poor inhibitors of rat renin and this has precluded the use of traditional rat models of hypertension. Sodium-depleted primates, generally marmosets or cynomologous monkeys, have been the animal models of choice. The development of double transgenic rats (dTGR) [33] and mice [34], expressing both human renin and human angiotensinogen, has provided a valuable alternative. These animals are markedly hypertensive and suffer end-organ damage resulting in death in
8 weeks. A range of tissue-specific mouse transgenes have been valuable in understanding the role of

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the RAS in end-organ damage. In addition to the RAS biomarkers mentioned above, studies in dTGR have also examined biomarkers for inflammation such as macrophage infiltration, which may be correlated with end-organ damage.

3. CLASSICAL RENIN INHIBITORS Intensive programs during the 1980s led to the discovery of many potent peptidomimetic renin inhibitors [6–9,35] e.g. remikiren (RO 42-5892, 1). During these efforts many of the now familiar peptide hydrolysis transition state isosteres, most of which position a hydroxyl group between the catalytic aspartates, were developed [36] and many potent inhibitors were discovered [6–9]. In 1, the P2 and P3 side chains are identical to those in the natural substrate angiotensinogen, while the cyclohexylmethyl group replaces i-Bu at P1. The molecule retains two peptidic secondary amides, has 4 stereocenters and its MW is 631. Remikiren has an IC50 of 0.7 nM against isolated renin and 0.8 nM in plasma; however, its oral bioavailability is o1%. Stepwise progress was made in reducing the peptidic character of the inhibitors [37,38] but in most cases vestiges of the peptidic backbone and sidechains were readily apparent, molecular weights were 4600 and oral bioavailability was inadequate. Compound 2 (BILA 2157 BS) is illustrative [39]: only a single secondary amide remains, the P2 group has been modified, the P3 group’s attachment point and identity has been changed and the compound has 40% oral bioavailability in cynomologous monkeys; however, the molecular weight is 726 and the compound retains 4 stereocenters. P2 NH2 HN

P4

N

N O

S

OH O

H N S O

O

OH H N

N

N H

N O

OH O

O

OH

N P3

P1

1

2

4. ALISKIREN 4.1. Aliskiren discovery The publication of the first X-ray structures of renin revealed the presence of a subpocket adjacent to S3, variously termed Saux or Ssp 3 3 , which is not filled by the natural substrate . SC-51106 (3) represents an early attempt to explore Ssp 3 with a methyl

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group [26]. The binding mode was confirmed by X-ray crystallography. SC-51106 has an IC50 of 11 nM, compared to 70 nM for desmethyl analog SC-47921 (4). HN N O N H R

OH

H N

O N

O

OH

3 R = Me 4 R=H

O

S

H N O

O

H N

N H

OH

O

OH

5

Examination of X-ray structures also made it clear that the S1 and S3 pockets of the enzyme are in fact contiguous and soon lead to attempts to fill S3 by attaching a substituent to the P1 group rather than from the peptide backbone [40–42]. Early compounds retained the peptide backbone with Gly replacing Phe. For example in 5, which has an IC50 of 11 nM, S1 and S3 are filled by a (4-(1-naphthyl) cyclohexyl)methyl group [40,41]. 6a R1 = H, R2 = Me, Q = Ph 6b R1 = Me, R2 = Me, Q = 1-naphthylCH2 6c R1 = Me, R2 = Me, Q = OH

Q

N O

H N

H2N O

6d R1 = Me, R2 = Me, Q =

CO2Me N O

R1 R2 OMe 6e R1 = H, R2 = Me, Q =

O O N H

Subsequently, the peptide backbone was dispensed with entirely leading, initially, to weakly active compounds, e.g. 6a IC50 ¼ 37 mM [43]. Optimization of this structural class, aided by X-ray crystallography, lead to several variations with improved potency: 6b IC50 ¼ 700 nM, 6c IC50 ¼ 52 nM, 6d IC50 ¼ 8 nM, 6e IC50 ¼ 22 nM [29,44,45]. Replacing the methyl group at R2 in 6e with an i-Pr group to give 7a further increased potency to 0.9 nM. Application of this modification to 6a and substitution of the phenyl ring with a 3-methoxypropoxy group at the 3-position and a methoxy group at the 4-position gave 7b IC50 ¼ 0.4 nM. Compounds 7a and 7b were less potent when assayed in the presence of plasma, with IC50s of 4 and 3 nM, respectively. Replacement of the n-Bu group on the prime side with various polar groups was explored in an attempt to alleviate the loss of potency in the presence of plasma ultimately leading to the discovery of

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aliskiren (8, SPP100) which has IC50s ¼ 0.6 nM against both purified human renin and plasma renin [46]. OH

H N

H2N

MeO

O

Q

OH

H N

H2N O

OMe

7a Q =

O

O

NH2 O

MeO MeO

O N H

7b Q =

8

O

MeO

The MW of aliskiren is 552 and at pH 7.4 it has a log Poctanol/water of 2.45 and water solubility of 350 mg/mL [46]. Its IC50 against porcine pepsin is 4100 mM, a substantially greater margin of selectivity than was seen with classical peptidomimetic renin inhibitors. Aliskiren does not inhibit CYP isozymes at 20 mM but is a weak inhibitor of CYP3A4, CYP2C9 and CYP2D6 at 200 mM. The molecule has 4 acyclic stereocenters and is synthetically challenging. The original synthesis described in the patent literature is 17 steps [47]. A number of groups have published alternative routes [48–53]. More recently, prodrugs of aliskiren in which the alcohol is acylated have been described in the patent literature [54]. In addition, analogs based on a diaminopropanol core, e.g. 9a IC50 ¼ 23 nM and 9b IC50 ¼ 71 nM, have been reported by two groups [55,56]. MeO

OH H2N O

H N

R O

MeO

9a R = CH2c-hex 9b R = CH2Ph

4.2. In vivo studies with aliskiren Aliskiren has been shown to lower blood pressure in sodium-depleted marmosets and in spontaneously hypertensive rats. In marmosets, a 10 mg/kg dose of aliskiren had an AUC of 49 mmol/l h and a mean t1/2 of 2.3 h quantitated by biological activity [57]. Its calculated oral bioavailability was 16.3%. The compound’s IC50 against marmoset renin is 2 nM and an oral dose of 3 mg/kg gave a 30-mmHg drop in blood pressure after 1 h and was more effective than the same dose of the older renin inhibitor 1. An oral dose of 10 mg/kg of aliskiren was at least as effective as valsartan and benazepril. Combinations of aliskiren with valsartan or benazeprilat, designed to block the RAS at multiple sites, lowered blood pressure more effectively

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than the individual drugs but caused significant increases in heart rate. In spontaneously hypertensive rats, a 30 mg/kg dose of aliskiren had lower AUC, shorter t1/2 and a calculated bioavailability of 2.4% [58]. Aliskiren is also effective in rats, however, higher doses were required, consistent with the aliskiren’s reduced potency against rat renin (IC50 ¼ 80 nM) and poorer pharmacokinetics. Subcutaneous administration of 0.3 mg/kg/day of aliskiren to dTGR lowered blood pressure by 63 mmHg and reduced albuminuria by 95% compared to untreated animals. All treated animals survived to 9 weeks and showed reductions in cardiac hypertrophy and other measures of cardiac damage and renal inflammation. In healthy, normotensive volunteers on a constant sodium diet, aliskiren is well tolerated over 8 days of dosing and gives a dose-dependent reduction in plasma renin activity, Ang I and Ang II, while levels of renin in plasma increased 16- to 34-fold [59]. No effect on blood pressure was observed in these normotensive volunteers. In 226 patients with mild to moderate hypertension, alsikiren was again well tolerated and effected-dose dependent reductions in blood pressure and plasma renin activity [60]. A 150 mg/day dose of aliskiren afforded an 11-mm Hg mean reduction in daytime ambulatory systolic pressure and a 77% reduction in plasma renin activity. The effects on blood pressure were very similar to those seen with a 100-mg dose of the ARB losartan. In another study of patients with mild to moderate hypertension, 150 mg/day of alsikiren reduced mean sitting diastolic and systolic blood pressure by 9.3 and 11.4 mmHg, respectively [61]. The ARB irbesartan at 150 mg/day gave similar results. In studies of the effect of coadministration of aliskiren with warfarin [62], lovastatin, atenolol, celecoxib and cimetidine [63] no significant pharmacokinetic interactions were observed. The bioavailability of aliskiren has been reported to increase when cyclosporin D, an efflux protein inhibitor, is coadministered [64].

5. PIPERIDINES High throughput screening uncovered trans-3,4-disubstituted piperidine 10a as the first representative of a new structural class of inhibitors [27,28]. The (R,R) isomer of 10a has an IC50 of 26 mM. A low resolution X-ray structure of the bromo analog 10b bound to human renin suggested that the piperidine nitrogen was positioned near the two catalytic aspartates and that the 3-, 4- and 5-positions of the piperidine ring could be substituted. Analog synthesis led to the substantially more potent 10c. The X-ray structure of 10c bound to renin showed that the 2-naphthylmethyl group occupied the S1 and S3 pockets and the substituent at the 4-position of the piperidine ring occupied a new pocket formed by opening of the flap and substantial changes in the positions of Tyr75 and Trp39. Further modification of 10c gave 11a and 11b, which has IC50s of 87 pM and 12 nM against purified human renin and plasma renin, respectively. Introduction of a polar 3-methoxy-2-hydroxypropyl chain at the 5-position of the piperidine ring gave 11c (RO0661132) with IC50s of 67 pM and 8.9 nM against purified human renin and plasma renin, respectively. When dosed orally in sodium-depleted marmosets at 100 mg/kg, the compound lowered pressure about as effectively as cilazapril at 3 mg/kg. When dosed at 30 mg/ kg/day in dTGRs, 11c produced substantial blood pressure lowering and also

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reduced cardiac hypertrophy, albuminuria, Ang-II induced end-organ damage and pro-inflammatory responses. H N H N

R1 O

R2 O

R R3 O

O

X

OMe

11a R1 = H, R2 = H, R3 = H 10 a X = Cl, R = 4-MeO-Bn 11b R1 = H, R2 = OMe, R3 = OMe 10 b X = Br, R = 4-MeO-Bn 1 2 3 10 c X = 2-Cl-C6H4C(=O)CH2, R = 2-naphthyl CH2 1 1c R = OCH2CH(OH)CH2OMe, R = H, R = OMe

Replacement of the naphthalene moiety of 11b with a tetrahydroquinoline ring gave 12a with IC50s of 0.67 and 37 nM against purified human renin and plasma renin, respectively [65]. The nitrogen atom of the tetrahydroquinoline ring provided an attachment point for the 2-(acetylamino)ethyl chain of 12b (RO0661168), which fills the Ssp 3 pocket and improves potencies against both purified and plasma renin to 39 pM and 0.6 nM, respectively [66], albeit with pharmacokinetic properties inferior to 11c. Both compounds were inhibitors of CYP3A4 [67]. Analogs of 11a in which the substituted naphthylmethoxy substituent at the 3- position0 of the piperidine ring is replaced by a naphthylmethylamino [30] have been reported, e.g. 13 IC50 ¼ 61 nM. Interestingly, in this series, the 3,4-cis stereochemistry is preferred. This series also inhibited CYP enzymes. Analogs in which the piperidine ring is bridged have been described in the patent literature: 14 is a preferred example [68]. H N H N

R

H N

N H

N

N O

N H

O F

O

O

O

O OMe

12a R = H 12b R = CH2CH2NHCOCH3

F

O

O

F

OMe

13

14

6. PIPERAZINES Introduction of a second nitrogen into the piperidine ring of 11a and moving the ether oxygen one position gave piperazine 15a IC50 ¼ 180 nM and ketopiperazine

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15b IC50 ¼ 54 nM [69,70]. Both these compounds were significantly less active than 11a but provided a novel scaffold for optimization. Compound 15b at 30 mg/kg was found to reduce blood pressure by up to 20 mmHg in double transgenic mice; however, blood pressure returned to baseline levels after 3 h. The most potent compounds in the series were 15c and 15d [71] with IC50s of 0.30 and 0.18 nM respectively; however, at 3 mM, both 15c and 15d inhibit CYP3A4 490%. In several cases, the R and S enantiomers in the ketopiperazine series were equipotent [72] . NHAc H N X

15c X = O, R = O

15a X = H2, R = O-(2-naphthyl)

N

R

N

15b X = O, R = O-(2-naphthyl) OMe

15d X = O, R = O

O

S

N

OMe

7. AMINOPYRIMIDINES Optimization of a 2,4-diaminopyrimidine HTS hit using a combination of parallel synthesis and X-ray crystallography afforded lead compound 16 IC50 ¼ 655 nM [73,74]. The 1-(3-methoxypropyl)-1,2,3,4-tetrahydroquinoline moiety of 16 was shown to occupy the S3 and Ssp 3 pockets of renin. Using NMR techniques, small molecules that could bind to the S2 pocket were identified and linked to 16 to give 17 IC50 ¼ 1 nM [75]. Further synthesis lead to 18 IC50 ¼ 1 nM, %F ¼ 8), 19 (IC50 ¼ 48 nM, %F ¼ 74) and 20 (IC50 ¼ 2 nM, %F ¼ 34) [76,77]. NH2

NH2

NH2

N

NH2 H N

N H

O

N

OMe O

S

NH2 O R

N

OMe O

O

O

F

16

17 F

18 R = NHAc 19 R = CH2CF3,(S)isomer 20 R = NHCO2Me

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8. CONCLUSION A decade after research into peptidomimetic renin inhibitors lost favor, several classes of non-peptidic inhibitors, including aliskiren, have been discovered. Potent examples of these classes contain basic amines that interact with the catalytic aspartates and structural elements that occupy Ssp 3 . Structure-based drug design has played an influential role in the discovery of these compounds.

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