title: Substrate analogue renin inhibitors containing replacements of histidine in P2 or isosteres of the amide bond between P3 and P2 sites.
abstract: Incorporation of beta-alanine or gamma-aminobutyric acid in position P2 of ACHPA or Leu psi [CHOHCH2]Val-based tetrapeptides gave highly active renin inhibitors (compounds V, VI, and XVII) with high specificity for renin and a remarkable stability against chymotrypsin. Replacement of the amide bond between P2 and P3 by isosteres (ketomethylenes, hydroxyethylenes, and the corresponding thio-insertion analogues) led to compounds (VIII-XIII, XVIII, and XIX) with renin inhibitory activity in the nanomolar range. Oral activity was achieved by incorporation of polar functionalities at the N-terminus of beta-alanine-containing tetrapeptides. One of these compounds (XXVIII) was chosen for further studies. This inhibitor demonstrated excellent efficacy and a long duration of action after intravenous and oral administration to cynomolgus monkeys.
authors.affiliation: E. Merck Darmstadt, Preclinical Pharmaceutical Research, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Raddatz
authors.forename: A
authors.initials: A
authors.lastname: Jonczyk
authors.forename: K O
authors.initials: KO
authors.lastname: Minck
authors.forename: C J
authors.initials: CJ
authors.lastname: Schmitges
authors.forename: J
authors.initials: J
authors.lastname: Sombroek
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006639:Histidine; D006801:Humans; D008252:Macaca fascicularis; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D006639:Histidine; D000092502:Renin Inhibitors