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  • 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.

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.

Journal of medicinal chemistry (2013-02-22)
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, Jürgen Maibaum
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 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Pyrrolidine, ≥99.0%
Sigma-Aldrich
Pyrrolidine, ≥99.5%, purified by redistillation
Sigma-Aldrich
Pyrrolidine, FG
Sigma-Aldrich
Pyrrolidine, 99%