An orally active renin inhibitor: cyclohexylnorstatine-containing dipeptide (KRI-1314).
In our continuing search for low molecular weight, human renin inhibitors, a dipeptide derivative, morpholino-naphthyl-acyl-histidyl-cyclohexyl-norstatine (KRI-1314), was newly synthesized and estimated for oral effectiveness. This compound inhibited plasma renin from humans and from Japanese monkeys in vitro, with 50% inhibitory concentrations (IC50) of 4.7 x 10(-9) and 2.4 x 10(-8) mol/l, respectively. The mean blood pressure of sodium-depleted Japanese monkeys was lowered significantly after intravenous injection or oral administration of KRI-1314. The maximum reduction was attained 3 h after oral administration at a dose of 10 mg/kg. Plasma renin activity (PRA) was halved 1 h after oral administration of KRI-1314, and this inhibition persisted for more than 5 h. results suggest that KRI-1314, a potent, orally effective and long-lasting renin inhibitor, may become one of a new class of antihypertensive agent.
Miyazaki
M
M
Department of Pharmacology, Osaka Medical College, Japan.
Etoh
Y
Y
Iizuka
K
K
Toda
N
N
D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D008251:Macaca; D008297:Male; D009025:Morpholines; D009281:Naphthalenes; D012083:Renin / Q000378:metabolism; D012964:Sodium / Q000172:deficiency; D000092502:Renin Inhibitors
D000959:Antihypertensive Agents; D004151:Dipeptides; D009025:Morpholines; D009281:Naphthalenes; D012083:Renin; D012964:Sodium; D000092502:Renin Inhibitors; C060500:KRI 1314