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Design and optimization of a substituted amino propanamide series of renin inhibitors for the treatment of hypertension |
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| Authors: | Austin Chen Christopher Bayly Olivier Bezençon Sylvia Richard-Bildstein Daniel Dubé Laurence Dubé Sébastien Gagné Michel Gallant Mireille Gaudreault Erich Grimm Robert Houle Patrick Lacombe Sébastien Laliberté Jean-François Lévesque Suzanna Liu Dwight MacDonald Bruce Mackay David Martin Dan McKay David Powell Sylvie Toulmond |
| Affiliation: | 1. Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Québec, Canada H9H 3L1;2. Merck Research Laboratories, Sumneytown Pike, PO Box 4, West Point, PA 19486, United States;3. Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland |
| Abstract: | The discovery and SAR of a new series of substituted amino propanamide renin inhibitors are herein described. This work has led to the preparation of compounds with in vitro and in vivo profiles suitable for further development. Specifically, challenges pertaining to oral bioavailability, covalent binding and time-dependent CYP 3A4 inhibition were overcome thereby culminating in the identification of compound 50 as an optimized renin inhibitor with good efficacy in the hypertensive double-transgenic rat model. |
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