The Discovery of Novel Potent trans-3,4-Disubstituted Pyrrolidine Inhibitors of the Human Aspartic Protease Renin from in Silico Three-Dimensional (3D) Pharmacophore Searches

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• 作者：Edwige Lorthiois ; Werner Breitenstein ; Frederic Cumin ; Claus Ehrhardt ; Eric Francotte ; Edgar Jacoby ; Nils Ostermann ; Holger Sellner ; Takatoshi Kosaka ; Randy L. Webb ; Dean F. Rigel ; Ulrich Hassiepen ; Paul Richert ; Trixie Wagner ; J眉rgen Maibaum
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 28, 2013
• 年：2013
• 卷：56
• 期：6
• 页码：2207-2217
• 全文大小：410K
• 年卷期：v.56,no.6(March 28, 2013)
• ISSN：1520-4804

文摘

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鈥搃nhibitor 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鈥?pockets of the recombinant human (rh)-renin active site was elucidated by X-ray crystallography. Initial structure鈥揳ctivity relationship work focused on modifications of the hydrophobic diphenylamine portion positioned in S1 and extending toward the S2 pocket. Replacement with an optimized P3鈥揚1 pharmacophore interacting to the nonsubstrate S3^sp 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.