title: 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.
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.
authors: Novartis Pharma AG, Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland. edwige.lorthiois@novartis.com
authors: Edwige
authors: E
authors: Lorthiois
authors: Werner
authors: W
authors: Breitenstein
authors: Frederic
authors: F
authors: Cumin
authors: Claus
authors: C
authors: Ehrhardt
authors: Eric
authors: E
authors: Francotte
authors: Edgar
authors: E
authors: Jacoby
authors: Nils
authors: N
authors: Ostermann
authors: Holger
authors: H
authors: Sellner
authors: Takatoshi
authors: T
authors: Kosaka
authors: Randy L
authors: RL
authors: Webb
authors: Dean F
authors: DF
authors: Rigel
authors: Ulrich
authors: U
authors: Hassiepen
authors: Paul
authors: P
authors: Richert
authors: Trixie
authors: T
authors: Wagner
authors: Jürgen
authors: J
authors: Maibaum
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D019295:Computational Biology; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011487:Protein Conformation; D011759:Pyrrolidines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012083:Renin / Q000737:chemistry; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D011480:Protease Inhibitors; D011759:Pyrrolidines; D012083:Renin; D000092502:Renin Inhibitors; C032519:pyrrolidine