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Discovery from in silico 3D Pharmacophore Searches of Novel 3(R),4(S)-disubstituted Pyrrolidine Inhibitors of the Human Aspartyl Protease Renin

Breitenstein, Werner and Cumin, Frederic and Ehrhardt, Claus and Jacoby, Edgar and Lorthiois, Edwige and Ostermann, Nils and Sellner, Holger and Kosaka, Takatoshi and Webb, Randy and Hassiepen, Ulrich and 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
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Additional Information: final draft submitted
Keywords: in silico 3D pharmacophore searches, renin inhibitor, 3(R),4(S)-disubstituted Pyrrolidine
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/3174

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