The Discovery
of Novel Potent <i>trans</i>-3,4-Disubstituted Pyrrolidine Inhibitors of the Human Aspartic Protease Renin from in Silico Three-Dimensional (3D) Pharmacophore Searches
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Abstract
The
small-molecule <i>trans</i>-3,4-disubstituted pyrrolidine <b>6</b> 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
(3<i>S</i>,4<i>S</i>)-<b>6a</b> 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<sup>sp</sup> cavity eventually
resulted in significantly improved in vitro potency and selectivity.
The prototype analogue (3<i>S</i>,4<i>S</i>)-<b>12a</b> of this new class of direct renin inhibitors exerted blood
pressure lowering effects in a hypertensive double-transgenic rat
model after oral administration