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. 2014 Apr 21;5(7):787–792. doi: 10.1021/ml500137b

Structure-Based Design of Substituted Piperidines as a New Class of Highly Efficacious Oral Direct Renin Inhibitors

Takeru Ehara †, Osamu Irie †, Takatoshi Kosaka †, Takanori Kanazawa †, Werner Breitenstein ‡, Philipp Grosche ‡, Nils Ostermann ‡, Masaki Suzuki †, Shimpei Kawakami †, Kazuhide Konishi †, Yuko Hitomi †, Atsushi Toyao †, Hiroki Gunji †, Frederic Cumin ‡, Nikolaus Schiering ‡, Trixie Wagner ‡, Dean F Rigel ∥, Randy L Webb ∥, Jürgen Maibaum ‡, Fumiaki Yokokawa †,*
PMCID: PMC4094259  PMID: 25050166

Abstract

graphic file with name ml-2014-00137b_0008.jpg

A cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a high-throughput screening hit from a target-family tailored library. Optimization of both the prime and the nonprime site residues flanking the central piperidine transition-state surrogate resulted in analogues with improved potency and pharmacokinetic (PK) properties, culminating in the identification of the 4-hydroxy-3,5-substituted piperidine 31. This compound showed high in vitro potency toward human renin with excellent off-target selectivity, 60% oral bioavailability in rat, and dose-dependent blood pressure lowering effects in the double-transgenic rat model.

Keywords: Renin inhibitor; structure-based design; aspartic protease; 3,5-piperidines

Hypertension is a major risk factor for cardiovascular diseases (CVDs), such as congestive heart failure, stroke, and myocardial infarction, which are the leading causes of death in industrialized countries. However, despite several classes of therapeutic drugs available, less than 30% of hypertensive patients achieve currently recommended blood pressure goals.1,2

The renin-angiotensin-aldosterone system (RAAS) has long been established as being the key cascade in the regulation of blood pressure and homeostasis of body fluid volume. Renin, an aspartic protease, cleaves angiotensinogen to release inactive peptide angiotensin I (Ang-I). Cleavage of Ang-I by angiotensin converting enzyme (ACE) then generates angiotensin II (Ang-II), which induces the principal physiological effects of the RAAS, i.e. an increase of blood pressure by vasoconstriction, sodium retention and altering vascular resistance.3 Renin controls the first and rate-limiting step of the RAAS and has high specificity for its substrate angiotensinogen. Blockade of renin has been considered to be a highly attractive paradigm to treat hypertension and to protect from end-organ damage.4

Since the early 1980s, substantial efforts had centered on peptidic or peptidomimetic scaffolds. However, these direct renin inhibitors (DRIs) suffered from lack of oral bioavailability and poor antihypertensive efficacy in clinical trials. To improve the unfavorable pharmacokinetic (PK) properties, a combination of crystallographic structure analyses and computational molecular modeling had been employed by Novartis to design nonpeptidic DRIs. This approach has led to the identification of aliskiren (Tekturna, Rasilez), a highly potent, selective, and long lasting antihypertensive DRI, which to date is the only marketed DRI for the treatment of hypertension.5,6 Subsequently, a number of DRIs based on diverse transition-state surrogate structural motifs and scaffolds with different renin active-site binding topology have been reported.7−9

As part of our continued research efforts to identify novel lead scaffolds, we have successfully applied complementary approaches including enzymatic high-throughput screens (HTSs), a combined NMR/X-ray fragment based screen,10 and in silico three-dimensional pharmacophore searches.11 Compound 1, a racemic cis-configured 3,5-disubstituted piperidine, originated as a weakly active HTS hit from a piperidine-based combinatorial library that had been specifically designed for aspartic proteases at Novartis (Figure 1).12 We previously reported that X-ray crystallography employing (rac)-1 and recombinant human renin (rh-renin) resulted in a complex structure with only the (3S,5R)-enantiomer of 1 bound in the active site and with the flap β-hairpin loop in a closed conformation (see Supporting Information, Figure S1). Subsequently, merging this piperidine scaffold with a second fragment-based screening hit led to (3S,5R)-2 with enhanced in vitro potency (IC50 = 3 nM).10 We report herein the results of an alternative approach to optimize screening hit 1, which led to the discovery of several potent and orally bioavailable DRIs.

Figure 1.

Figure 1

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Discovery of (rac)-6 from the HTS hit (syn,rac)-1.

Initially, the highly lipophilic diphenylmethylamine P3–P1 pharmacophore of 1 was replaced by the N-cyclopropyl N-dichlorobenzyl amide motif, previously reported for 3,4-piperidine-based DRIs to fill the large contiguous S3–S1 binding pocket,13 to provide (rac)-3 (Figure 1). Replacement of the C5-sulfonamide spacer by a carbamate linker identified the 10-fold more potent (rac)-4. The X-ray cocrystal structure of (rac)-4 with rh-renin showed only the (3R,5S)-enantiomer bound, opposite to the observation made for (rac)-1 (see Supporting Information, Figure S1). With the aim of improving potency by filling the nonsubstrate S3 subpocket (S3sp), extending perpendicular from the S3 pocket, we next replaced the dichlorophenyl moiety by an indole scaffold substituted at the ring nitrogen by a methoxypropyl side chain14 to afford (rac)-5. Further optimization of (rac)-5 by introduction of the reversed amide spacer at the 5-position of the central piperidine provided (rac)-6, exhibiting a marked increase in potency. Computational modeling suggested that the higher inhibitory affinity is due to the reversed amide carbonyl group forming an H-bond to the backbone nitrogen of Ser76 of the flap β-hairpin.15

We next investigated the optimization of the C5-amide moiety with various α-branched amines occupying the S1′-S2′ pockets (Table 1). Incorporation of an H-bond donor or acceptor into the prime-site amide moiety was anticipated to target an H-bond with Gly34 as well as to reduce lipophilicity, thereby increasing plasma renin potency. Indeed, compounds 8 and 9 displayed IC50 values of 8 and 1 nM, respectively, in the presence of plasma. However, these compounds suffered from low oral bioavailability in rat (<1%) with medium clearance in rat liver microsomes (RLM). An o,o-disubstituted aniline moiety was also found to fill the prime-site efficiently, however, compound 10 showed high in vitro clearance. In addition, we noticed that the potential for metabolism of the 3-aminomethylindole moiety could lead to generation of a reactive electrophilic intermediate.16 We therefore returned our focus to alternative P3–P1 moieties.

Table 1. Optimization of the C5-Amide Moiety Filling the S1′-S2′ Pockets.

graphic file with name ml-2014-00137b_0006.jpg

cmpda renin IC50 (nM) (buffer/plasma) in vitro CLint (μL/min/mg, human/rat) rat F (%) (i.v./p.o. 2/6 mg/kg)
7 3/40 194/141 29
8 3/8 157/111 0.4
9 0.4/1 173/109 <0.1
10 0.4/2 679/533 nd
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a

All compounds were used as their free base.

At this stage, the development of a versatile synthetic route was required to facilitate optimization of both the prime- and the nonprime binding motifs (Scheme 1). We established a stereoselective synthesis of both (S,R)- and (R,S)-configured cis-piperidine enantiomers 12 and 13 based on an asymmetric desymmetrization approach starting from the meso-cyclic anhydride 11.17 Cinchona base-catalyzed methanolysis of 11, followed by recrystallization with (R)- and (S)-1-phenylethylamine provided the enantiomerically pure 3,5-piperidine carboxylic acids (3S,5R)-12 and (3R,5S)-13 with >99% ee, respectively.18 Subsequent amide coupling of (3S,5R)-12 with sterically hindered N-cyclopropyl anilines required extensive optimization. A mixed anhydride coupling method using TcBocCl (2,2,2-trichloro-1,1-dimethylethyl chloroformate) in the presence of magnesium bromide proved optimal in providing amides 14. Alkaline hydrolysis followed by coupling to the prime-site moiety afforded intermediates 16. N-Boc deprotection using HCl gave the target products 17. Similarly, the reversed order of coupling steps starting from (3R,5S)-13 could be employed.

Scheme 1. Stereoselective Synthesis of 3,5-Piperidine Analogues.

Scheme 1

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Reagents and conditions: (a) MeOH, (DHQ)2AQN, 95%, 63% ee; (b) recrystallization with (R)-1-phenylethylamine, >99% ee; (c) MeOH, (DHQD)2AQN, 91%, 75% ee; (d) recrystallization with (S)-1-phenylethylamine, >99% ee; (e) TcBocCl, Et3N, CH3CN then ArR1-NH, MgBr2; (f) aq. LiOH, THF; (g) R2-NH2, EDCI·HCl, HOAt, DMF; (h) HCl in dioxane; (i) R2-NH2, EDCI·HCl, HOAt, DMF; (j) aq. LiOH, THF; (k) ArR1-NH, BopCl, Et3N, CH2CH2; (l) HCl in dioxane.

Next, we revisited the N-cyclopropyl N-dichlorobenzyl amide P3–P1 binding motif. Modeling and SAR studies led to replacement of the 3-aminomethylindole with 4-isopropyl-3-(3-methoxypropoxy)anilide. Compound 21 afforded IC50s of 0.3 and 2.0 nM against rh-human renin in buffer and in the presence of plasma, respectively (Table 2). The potency of 21 is believed to be a result of the fluorine atom forming an H-bond with the hydroxyl group of Thr77. Unfortunately, inhibitor 21 suffered from high clearance in RLM as well as hERG binding, presumably due to the more lipophilic character of the molecule. We therefore explored the less hydrophobic 1,4-benzoxazinone motif as a P3 pharmacophore.19 Inhibitor 22 (Table 2) showed not only high in vitro potency but also high clearance in RLM, translating into high in vivo clearance in rat. Replacement of the 6-fluoroaniline with 6-aminopyridine offered an alternative H-bond acceptor for Thr77, and also reduced the lipophilicity. As a result, the 6-aminopyridine P3 pharmacophore in 23 retained high potency while improving in vitro and in vivo clearance in rats. The regioisomeric 2-aminopyridine analogue 24 was found to be less potent and metabolically less stable than 23. We suspected that the S3sp-filling alkoxy side chain of 23 potentially constitutes a metabolically weak spot, and furthermore that its high number of rotatable bonds may limit cell permeability. Truncation of the S3sp side chain provided 25 and 26, which were found to retain high in vitro potency despite the suboptimal occupancy of S3sp. Most remarkably, the P3-aminopyridine analogue 27 bearing no side chain at the C4 position still exhibited high in vitro potency, while the corresponding P3-aniline analogue 28 was 4 and >1000-fold less active in the buffer and plasma renin assays, respectively. These results suggested that the H-bond interaction of the P3-pyridyl nitrogen atom with the OH of Thr77 fully compensates for the lack of binding interactions to the S3sp cavity. In addition, the more hydrophilic P3-aminopyridine moiety led to a reduction in the plasma IC50 shift. Compound 27 also showed improved in vitro metabolic stability and oral bioavailability in the rat. However, 27 (logD (pH 6.8) = 4.9) showed modest affinity to the hERG channel as determined by a dofetilide binding assay,20 as compared to the less hydrophobic compounds 25 (logD (pH 6.8) = 2.2) and 26 (logD (pH 6.8) = 2.1). Therefore, introduction of a polar hydroxyl group to the 4-position of the central piperidine ring was investigated. Inhibitors 29, 30 and 31 (logD (pH 6.8) = 0.93) all retained the in vitro inhibitory potency against human renin as well as a favorable hERG profile. These 4-OH analogues also showed better oral bioavailability compared to their corresponding nonhydroxylated analogues (25, 26 and 27, respectively, Table 2).

Table 2. SAR Data for Inhibitors Modified at P3−P1, including in Vivo Rat Pharmacokinetics (PK) (i.v. 2 mg/kg, p.o. 6 mg/kg).

graphic file with name ml-2014-00137b_0007.jpg

      i.v. PK parametersb
 p.o. PK parametersb
  
cmpd renin IC50 (nM) (buffer/plasma)a in vitro CLint (μL/min/mg, human/rat)a CL (L/h/kg) Vdss (L/kg) T1/2 (h) oral Cmax/dose (nM/mg/kg) oral AUCinf./dose (nM*h/mg/kg) F (%) hERGbind. IC50 (μM)a
21 0.3/2.0 115/214 nd nd nd nd nd nd 5.5
22 0.3/3.0 61/198 7.3 12 1.9 12 49 20 >30
23 0.4/1.0 53/96 4.8 11 4.3 18 93 19 >30
24 0.8/6.0 289/252 nd nd nd nd nd nd 3.3
25 0.2/0.4 15/101 2.4 4.3 7.0 68 324 39 >30
26 0.2/0.6 46/62 1.4 4. 6 7.4 155 690 44 >30
27 0.9/1.1 <3.4/13 3.6 7.2 6.5 63 296 45 7
28 4.0/5340 nd/nd nd nd nd nd nd nd nd
29 0.8/2.0 22/142 2.4 6.1 7.7 74 511 61 >30
30 0.6/2.5 22/54 0.74 2.6 5.9 252 1630 60 >30
31 0.2/0.6 <3.4/52 2.4 4 6.8 136 552 61 >30
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a

Determined for the HCl salt of each compound.

b

The following salts were used for in vivo PK studies in rat: 22, HCl; 23, HCl; 25, tartrate; 26, tartrate; 27, fumarate; 30, fumarate; 31, succinate; inhibitor 29 was administered as its free base.

The synthesis of inhibitors bearing the core (3S,4S,5R)-4-hydroxy-3,5-piperidine scaffold started from (3S,4S,5R)-32, which was obtained by the published procedure,21 followed by recrystallization with (R)-1-phenylethylamine to increase the enantiomeric excess to >99%. Amide coupling of 32 with the respective P3–P1 anilines was carried out using acid chloride or TcBocCl mediated activation of the carboxylic acid function. Alkaline ester hydrolysis of the resulting intermediate 33, followed by the second amide coupling step to attach the prime-site moiety and deprotection afforded inhibitors 36 (Scheme 2).

Scheme 2. Stereoselective Synthesis of 4-Hydroxy-3,5-piperidine Analogues.

Scheme 2

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Reagents and conditions: (a) (i) (1-chloro-2-methylpropenyl)-dimethylamine, CH2Cl2 or TcBocCl, Et3N, THF, (ii) P1–P3 amine, MgBr2 (for TcBoc method); (b) aq. LiOH, THF; (c) R′-NH2, EDCI·HCl, HOAt, DMF; (d) HCl in dioxane.

Inhibitor 31 was selected for further in vitro and in vivo evaluation based on its overall attractive profile. The compound was highly selective against a panel of recombinant human aspartic proteases comprising pepsins A and C, cathepsins D and E, as well as BACE 1 and BACE 2 (all IC50s >30 μM). Furthermore, high selectivity over a panel of >60 receptors, ion channels, and enzymes including CYP3A4, 2C9, and 2D6 (all IC50 >30 μM) was achieved. Parent 31 as well as the corresponding aminopyridine P3–P1 fragment were nonmutagenic in the Ames test, both in the presence and absence of S9 mix. Compound 31 exhibited weak inhibitory activity against hERG, as well as the cardiac sodium (Nav1.5) and L-type calcium (Cav1.2) channels (IC50s of >30 μM) as measured by in vitro patch clamp assays. The succinate salt is crystalline (mp 122 °C), chemically stable in bulk during 3 days at 80 °C, and highly soluble in water at the pH range between 1 and 9 (>10 mg/mL). Single oral dosing of 31 as its succinate salt to telemetered double-transgenic rats (dTGRs)22 at 1, 3, 10, 30, and 100 mg/kg resulted in a dose-dependent and long-lasting reduction in mean arterial blood pressure (MAP) with peak changes in MAP of 33, 42, 52, 63, and 66 mmHg, respectively (Figure 2). Remarkably, a significant blood pressure lowering effect was still observed 42 h after the 100 mg/kg oral dose was administered.

Figure 2.

Figure 2

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In vivo blood-pressure lowering oral efficacy of 31 (succinate salt) in telemetered dTGRs.

The crystal structure of rh-renin in complex with 31 revealed the ligand to bind in an extended conformation, occupying the S3 to S2′ site of the enzyme active site (Figure 3). The basic nitrogen atom of the piperidine ring interacts with both catalytic aspartic acid residues, Asp32 and Asp215, which functions as a transition-state surrogate. The 4-hydroxyl group is H-bonded to Ser76 of the flap being in a closed conformation.23 The N-cyclopropyl group and the isopropyl-substituted pyridyl moiety are positioned in the large contiguous hydrophobic S1/S3 pocket, leaving the S3sp unoccupied. The pyridyl nitrogen is in close H-bond distance to the side chain hydroxyl of Thr77 located at the tip of the flap domain. The data support the notion that this interaction is indeed crucial for strong binding affinity, in particular for inhibitors lacking interactions with the S3sp site. The carbonyl oxygen of the prime-site amide linker forms an H-bond to the backbone nitrogen of the flap Ser76, while the amide NH functions as an H-bond donor to the carbonyl oxygen of Gly34. The sec-butyl makes hydrophobic interactions to S1′, and the terminal ethoxyethane group occupies the S2′ pocket.

Figure 3.

Figure 3

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Crystal structure of 31 (shown as a stick model in cyan color; PDB code 4Q1N) bound to rh-renin. Shown is the solvent accessible surface of the active site of renin, the catalytic aspartate residues Asp32 and Asp215, as well as the residues of the flap β-hairpin with carbon atoms colored in gray. The flap residues Tyr75, Ser76, Thr77, and Gly78 have been omitted from the protein surface calculation. The oxygen and nitrogen atoms are colored in red and blue, respectively.

In summary, novel highly potent cis-configured (3R,5S)-piperidine-based DRIs were derived from a weakly active HTS hit (compound 1). Structure-based modification of the prime-site linker and optimization of the P3–P1 and P1′-P2′ portions guided by X-ray crystallography significantly improved the in vitro potency. The discovery of the N-alkyl substituted 6-pyridyl as a novel high affinity P3 scaffold even in the absence of a P3sp side chain constituted a breakthrough of our extensive optimization efforts. The additional introduction of a hydroxyl group on the piperidine core furnished several inhibitors with improved PK profiles in rats. Inhibitor 31 demonstrated high in vitro potency and off-target selectivity, an attractive physicochemical and in vitro ADME profile, as well as excellent oral bioavailability and long elimination half-life in rat. Inhibitor 31 showed high efficacy in the dTGR model with a dose-dependent sustained blood pressure reduction observed for more than 24 h after single oral dose administration.

Acknowledgments

We thank Hans-Peter Baum and Markus Sanner for IC50 determinations of renin inhibition and Marie-Helene Bellance, Corinne Durand, and Paul Schultheiss for their technical assistance. We thank Florence Zink and Allan D’Arcy for protein crystallization. We also thank Masashi Furuichi and Oliver Grosche for measuring the melting point and aqueous solubility of 31 succinate. We acknowledge Virginia Casadas for her dTGR study with 31, and Charles Babu and Bin Wang for their support in NMR studies. We thank Leslie Bell, Susanne Glowienke, Martin Traebert, Steven Whitebread, and their team members for their help in getting the profiling data of 31. We thank Jason Elliott and Christopher M. Adams for their critical reading of the manuscript.

Glossary

Abbreviations

RAAS

renin–angiotensin–aldosterone system

ACE

angiotensin converting enzyme

ADME

absorption, distribution, metabolism, and excretion

DRI

direct renin inhibitor

HTS

high-throughput screening

rh-renin

recombinant human renin

Ac2O

acetic anhydride

Boc

tert-butoxycarbonyl

(Boc)2O

di-tert-butyl dicarbonate

BopCl

bis(2-oxo-3-oxazolidinyl)phosphinic chloride

DMF

dimethylformamide

dTGR

double transgenic rat

EDCI·HCl

1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride

Et3N

triethylamine

EtOAc

ethyl acetate

EtOH

ethyl alcohol

hERG

the human ether-à-go-go-related gene

HOAT

1-hydroxy-7-azabenzotriazol

mp

melting point

PK

pharmacokinetics

RLM

rat liver microsomes

TcBocCl

2,2,2-trichloro-1,1-dimethylethyl chloroformate

Supporting Information Available

Full experimental details for compounds synthesized, experimental procedures for biological assays, in vivo pharmacokinetics, in vivo pharmacology, and X-ray crystallographic information for the rh-renin–inhibitor complexes. This material is available free of charge via the Internet at http://pubs.acs.org.

Author Present Address

§ Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, Massachusetts 02139, United States

Author Present Address

⊥ Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670.

The authors declare no competing financial interest.

Supplementary Material

ml500137b_si_001.pdf (1.2MB, pdf)

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Associated Data

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Supplementary Materials

ml500137b_si_001.pdf (1.2MB, pdf)

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