Breitenstein, Werner, Cumin, Frederic, Ehrhardt, Claus, Jacoby, Edgar, Lorthiois, Edwige, Ostermann, Nils, Sellner, Holger, Kosaka, Takatoshi, Webb, Randy, Hassiepen, Ulrich, Wagner, Beatrix and Maibaum, Juergen Klaus (2013) Discovery from in silico 3D Pharmacophore Searches of Novel 3(R),4(S)-disubstituted Pyrrolidine Inhibitors of the Human Aspartyl Protease Renin. Journal of Medicinal Chemistry, 56 (6). pp. 2207-2217. ISSN 0022-2623

Abstract

The small-molecule trans-3,4-disubstituted pyrrolidine 6 was identified from in silico three-dimensional (3D) pharmacophore searches based on known X-ray structures of renin-inhibitor complexes and demonstrated to be a weakly active inhibitor of the human enzyme. The unexpected binding mode of the more potent enantiomer (3S,4S)-6a in an extended conformation spanning the nonprime and S1' pockets of the recombinant human (rh)-renin active site was elucidated by X-ray crystallography. Initial structure-activity relationship work focused on modifications of the hydrophobic diphenylamine portion positioned in S1 and extending toward the S2 pocket. Replacement with an optimized P3-P1 pharmacophore interacting to the nonsubstrate S3sp cavity eventually resulted in significantly improved in vitro potency and selectivity. The prototype analogue (3S,4S)-12a of this new class of direct renin inhibitors exerted blood pressure lowering effects in a hypertensive double-transgenic rat model after oral administration.

Item Type:	Article
Related URLs:	Publisher Publisher
Additional Information:	final draft submitted
Keywords:	in silico 3D pharmacophore searches, renin inhibitor, 3(R),4(S)-disubstituted Pyrrolidine
Related URLs:	Publisher Publisher
Date Deposited:	13 Oct 2015 13:16
Last Modified:	13 Oct 2015 13:16
URI:	https://oak.novartis.com/id/eprint/3174