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

Abstract

A cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a highthroughput 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 H ypertension 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. 1,2The 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 pharmacoph...

Discovery of 18F-JK-PSMA-7, a PET Probe for the Detection of Small PSMA-Positive Lesions

“…18 F-JK-PSMA-14 ( 18 F-11) was prepared as described elsewhere (17). The preparation of intermediates, precursors for radiolabeling, and reference compounds is shown in the supplemental data or was previously published (18)(19)(20)(21)(22).…”

Discovery of TAK-272: A Novel, Potent, and Orally Active Renin Inhibitor

“… 10 , 11 Additionally, it has been demonstrated by others that occupation of the S1′ site can lead to enhancement of potency. 13 , 14 Thus, we investigated the introduction of additional substituents directed toward the S1′ site to enhance potency.…”

“…The morpholinocarbonyl group occupies the S1′ site, as we predicted. 13 , 14 , 19 Furthermore, its carbonyl oxygen atom forms a hydrogen bond with the backbone amino group of Ser76 on the flap being in a closed conformation. 13 , 14 These interactions would be expected to contribute to the improvement in renin inhibitory activity.…”

“…The X-ray cocrystal structure of compound 1 bound to renin was examined in detail as the starting point for our next round of SBDD efforts (Figure ). The contiguous lipophilic S3 and S1 sites are occupied by the tert -butylpyrimidine and isobutyl moieties with the flap β-hairpin in a closed conformation. , The piperidine NH group makes a salt bridge with the residues of Asp32 and Asp215, and the S3 sp site is occupied by the furfurylamine moiety. The amino group at the pyrimidine 4-position forms a hydrogen bonding interaction with backbone of Gly217.…”

Theoretical prediction on the synthesis of 2,3‐dihydropyridines through Co(III)‐catalysed reaction of unsaturated oximes with alkenes

“…2,3‐Dihydropyridines are not found in bioactive molecules due to their kinetic instabilities. However they are regarded as versatile intermediates in biosynthetic methodology, and can be reduced to piperidines which are important building blocks for numerous pharmaceuticals . Recently, Rovis and coworkers reported the synthesis of 2,3‐dihydropyridines through Cp*Rh(III) complex‐catalysed reaction of unsaturated oximes with alkenes, featuring a broad range of substrates and high diastereoselectivity .…”