title: Kinetics of the inhibition of human renin by an inhibitor containing a hydroxyethylene dipeptide isostere.
abstract: We have studied the inhibition of both human and hog renins by compound 1 [Boc-Pro-Phe-N alpha-MeHis-Leu psi(CHOHCH2)Val-Ile-(aminomethyl)pyridine] using kinetics. The inhibition of human renin was shown to be time dependent and followed a minimal two-step mechanism. A loosely bound EI complex was formed rapidly with a dissociation constant, KI, of 12 nM. A second EI complex was slowly formed and was found to be 64-fold more strongly bound with an overall KI of 0.19 nM. The inhibition of human renin was shown to be competitive by both initial and final steady-state velocities. Compound 1 was also shown to be a competitive inhibitor of hog renin with a KI of 12 nM, but no evidence for time-dependent inhibition was detected. The differences in overall KI and inhibition kinetics may be a consequence of the similarities in structure between 1 and human angiotensinogen.
authors.affiliation: Cardiovascular Diseases Research, Upjohn Company, Kalamazoo, Michigan 49001.
authors.forename: W M
authors.initials: WM
authors.lastname: Kati
authors.forename: D T
authors.initials: DT
authors.lastname: Pals
authors.forename: S
authors.initials: S
authors.lastname: Thaisrivongs
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D006801:Humans; D007700:Kinetics; D009842:Oligopeptides / Q000494:pharmacology*; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013045:Species Specificity; D013552:Swine; D000092502:Renin Inhibitors
chemical_list: D009842:Oligopeptides; D012083:Renin; D000092502:Renin Inhibitors; C050898:ditekiren