Sellner, Holger, Cottens, Sylvain, Cumin, Frederic, Ehrhardt, Claus, Kosaka, Takatoshi, Lorthiois, Edwige, Ostermann, Nils, Webb, Randy, Rigel, Dean, 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