Ehara, Takeru, Kosaka, Takatoshi, Kanazawa, Takanori, Grosche, Philipp, Ostermann, Nils, Cumin, Frederic, Schiering, Nikolaus, Rigel, Dean, Webb, Randy, Maibaum, Juergen Klaus, Yokokawa, Fumiaki, Irie, Osamu Irie, Breitenstein, Werner , Suzuki, Masaki , Kawakami, Shimpei , Konishi, Kazuhide , Hitomi, Yuko , Toyao, Atsushi and Gunji, Hiroki (2014) Structure-based Design of 4-Hydroxy-3,5-Substituted Piperidines as a New Class of Highly Efficacious Oral Direct Renin Inhibitors. ACS Medicinal Chemistry Letters, 5 (7). pp. 787-792.

Abstract

Starting from the cis-configured 3,5-disubstituted piperidine direct renin inhibitor (DRI), (rac)-1, discovered from a target-family-tailored library by high throughput screening (HTS), a structure-based design effort was performed by optimization of both the prime and non-prime site residues flanking the central piperidine transition-state surrogate. This has resulted in analogs with improved potency and pharmacokinetic (PK) properties, and culminated in the identification of the 4-hydroxy-3,5-substituted piperidine, 35 as a development candidate. 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.

Item Type:	Article
Keywords:	Renin inhibitor; structure-based design; aspartic protease; 3,5-piperidines
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/20958