title: KRI-1314: an orally effective inhibitor of human renin.
abstract: Biochemical and pharmacological properties of KRI-1314, a newly synthesized, low molecular weight (M.W.: 690) renin inhibitor, were investigated in vitro and in vivo. The novel amino acid norstatine, which is shorter in chain length than the well-known statine, was incorporated into KRI-1314 as a tetrahedral transition-state analogue for the Leu10-Val11 scissile peptide in the renin substrate. KRI-1314 more strongly inhibited plasma renins from primates than those from dogs, rabbits, guinea pigs and rats. KRI-1314 competitively inhibited highly-purified human renin with a Ki value of 9.9 x 10(-10) M. KRI-1314 strongly inhibited the tissue renin-like activities of various organs from Japanese monkeys, with IC50 values on the order of 10(-8) M. KRI-1314 was also very stable in various tissue homogenates from Japanese monkeys. Both intravenous (from 0.25 to 3 mg/kg) and oral (10 and 30 mg/kg) administration of KRI-1314 to anesthetized and conscious sodium-depleted Japanese monkeys, respectively, significantly lowered the blood pressure and plasma renin activity without affecting the heart rate. In Japanese monkeys, KRI-1314 was continuously detected in the plasma up to at least 7 hr after oral administration of 10 and 30 mg/kg. These results demonstrate that KRI-1314 is a highly potent, primate-selective and long-lasting oral renin inhibitor with a blood pressure lowering effect.
authors.affiliation: Department of Pharmacology, Osaka Medical College, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Etoh
authors.forename: M
authors.initials: M
authors.lastname: Miyazaki
authors.forename: H
authors.initials: H
authors.lastname: Saitoh
authors.forename: N
authors.initials: N
authors.lastname: Toda
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008251:Macaca; D008297:Male; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D012083:Renin / Q000097:blood / Q000378:metabolism; D014018:Tissue Distribution; D000092502:Renin Inhibitors
chemical_list: D004151:Dipeptides; D009025:Morpholines; D009281:Naphthalenes; D012083:Renin; D000092502:Renin Inhibitors; C060500:KRI 1314