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Trans-3,4-Disubstituted Pyrrolidines as Inhibitors of the Human Aspartyl Protease Renin. Part II: Ether and Carbamate Prime Site Derivatives

Sellner, Holger and Cottens, Sylvain and Cumin, Frederic and Ehrhardt, Claus and Kosaka, Takatoshi and Lorthiois, Edwige and Ostermann, Nils and Webb, Randy and Rigel, Dean and Wagner, Beatrix and Maibaum, Juergen Klaus (2015) Trans-3,4-Disubstituted Pyrrolidines as Inhibitors of the Human Aspartyl Protease Renin. Part II: Ether and Carbamate Prime Site Derivatives. Bioorganic and Medicinal Chemistry Letters, 25 (8). pp. 1787-1791. ISSN 0960894X

Abstract

Inhibition of the aspartyl protease renin is considered as an efficient approach for treating hypertension. Lately, we described the discovery of a novel class of direct renin inhibitors which comprised a pyrrolidine scaffold (e.g. 2). Based on the X-ray structure of the lead compound 2 bound to renin we reckoned that optimization of binding interactions to the prime site could offer an opportunity to further expand the scope of this chemotype. Pyrrolidine-based inhibitors were synthesized in which the prime site moieties are linked to the pyrrolidine core through an oxygen atom, resulting in an ether or a carbamate linker subseries, respectively. Especially the carbamate derivatives showed a pronounced increase in in vitro potency compared to 2. Here we report the structure-activity relationship of both subclasses and demonstrate blood pressure lowering effects for an advanced prototype in a hypertensive double-transgenic rat model after oral dosing.

Item Type: Article
Keywords: Direct renin inhibitor Structure guided drug design pyrrolidine in vivo potency
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/24499

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