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

Ehara, Takeru and Kosaka, Takatoshi and Kanazawa, Takanori and Grosche, Philipp and Ostermann, Nils and Cumin, Frederic and Schiering, Nikolaus and Rigel, Dean and Webb, Randy and Maibaum, Juergen Klaus and Yokokawa, Fumiaki and Irie, Osamu Irie and Breitenstein, Werner and Suzuki, Masaki and Kawakami, Shimpei and Konishi, Kazuhide and Hitomi, Yuko and 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

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