Structure-based Design of 4-Hydroxy-3,5-Substituted Piperidines as a New Class of Highly Efficacious Oral Direct Renin Inhibitors
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 |
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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 |