title: CP-71,362: a pentapeptide renin inhibitor selective for the canine enzyme.
abstract: Most renin inhibitors are primate-specific. In the present paper, we describe the effects of CP-71,362, a pentapeptide which preferentially inhibits canine (and to a lesser extent, rat) plasma renin. Vs. the canine enzyme, its affinity (IC50 = 3.3 x 10(-12) M) is 1000x greater than for rat renin (IC50 = 3.3 x 10(-9) M), and 1000x greater than for human (IC50 = 2.3 x 10(-8) M), cynomolgus monkey (IC50 = 1.6 x 10(-8) M), or guinea pig (IC50 = 5.2 x 10(-8) M) enzyme. In anesthetized, sodium-depleted dogs, intravenous infusion of CP-71,362 (ED50 = 1.1 micrograms/kg/min) resulted in dose-dependent decreases (up to -35 mm Hg) in mean arterial pressure (MAP). The maximum fall in MAP was equivalent to that produced by i.v. captopril (5 mg/kg). Similar falls in MAP were observed in conscious sodium-depleted SHR (ED50 = 5 micrograms/kg/min). Via bolus injection, the action of CP-71,362 was relatively brief in dog, guinea pig, and SHR. We conclude that CP-71,362 is a potent canine/rat renin inhibitor and causes profound MAP lowering in these species.
authors.affiliation: Department of Cardiovascular and Metabolic Diseases, Pfizer Central Research, Groton, CT 06340.
authors.forename: M L
authors.initials: ML
authors.lastname: Mangiapane
authors.forename: J T
authors.initials: JT
authors.lastname: MacAndrew
authors.forename: S S
authors.initials: SS
authors.lastname: Ellery
authors.forename: A H
authors.initials: AH
authors.lastname: Smith
authors.forename: I M
authors.initials: IM
authors.lastname: Purcell
authors.forename: E F
authors.initials: EF
authors.lastname: Kleinman
authors.forename: W F
authors.initials: WF
authors.lastname: Holt
authors.forename: W R
authors.initials: WR
authors.lastname: Murphy
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002216:Captopril / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D008252:Macaca fascicularis; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D012083:Renin / Q000097:blood; D000092502:Renin Inhibitors
chemical_list: D002216:Captopril; D009842:Oligopeptides; D012083:Renin; D000092502:Renin Inhibitors; C060149:CP 71362