indolapril-hydrochloride and Hypertension--Renovascular

CI-907 is a new orally active nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor. Monoester (prodrug) and diacid forms produced concentration related ACE inhibition in guinea-pig serum (IC50 for monoester, 1.7 X 10(-7) M and for diacid, 2.6 X 10(-9) M). In isolated rabbit aortic rings and in rat and dog autonomic studies, CI-907 is highly specific in suppressing the contractile or pressor responses to angiotensin I. In two-kidney, one-clip Goldblatt hypertensive rats, single daily doses (0.03-30 mg/kg p.o.) produced dose-dependent decreases in blood pressure; 3 mg/kg lowered blood pressure to normotensive levels. In the spontaneously hypertensive rat, subacute administration of CI-907 (30 mg/kg/day for 5 days) produced the same decrease in blood pressure as that obtained in the renal hypertensive rat. In diuretic-pretreated renal hypertensive dogs, 10 mg/kg normalized blood pressure. For equivalent drops in blood pressure, heart rate increases were less in CI-907 than in enalapril-treated renal hypertensive dogs. No side effects were observed with CI-907 in any of the conscious animals. The antihypertensive response to CI-907 (0.03-1.0 mg/kg p.o.) was found to correlate with inhibition of vascular tissue ACE, but not plasma or brain ACE in two-kidney, one-clip renal hypertensive rats. These studies indicate that CI-907 is a potent antihypertensive agent with a heart rate profile different from enalapril.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Dipeptides; Dogs; Dose-Response Relationship, Drug; Enalapril; Heart Rate; Hypertension, Renovascular; Indoles; Rats; Rats, Inbred Strains; Time Factors

CI-906 and CI-907, new orally active nonsulfhydryl angiotensin-converting enzyme inhibitors, were examined for antihypertensive effects in unanesthetized hypertensive rats and dogs. In two-kidney, one-clip Goldblatt hypertensive rats, single oral daily doses (0.03-30 mg/kg) produced dose-dependent decreases in blood pressure; a single 3 mg/kg oral dose lowered blood pressure to normotensive levels. In spontaneously hypertensive rats, 30 mg/(kg X day) orally administered for 5 consecutive days achieved the same blood pressure decrease as that obtained on the first day in the renal hypertensive rats. In diuretic-pretreated renal hypertensive dogs, a 10 mg/kg oral dose decreased blood pressure by 25%. No adverse side effects were observed with CI-906 and CI-907 in any of the conscious animals. These studies indicate that CI-906 and CI-907 are potent, orally active antihypertensive agents without any apparent limiting side effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Captopril; Dipeptides; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Enalapril; Female; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Indoles; Isoquinolines; Kinetics; Male; Quinapril; Rats; Rats, Inbred Strains; Renin-Angiotensin System; Tetrahydroisoquinolines

CI-906, [3S-[2[R*(R*)]], 3R*]-2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]-amino]-1-oxopropyl] 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, monohydrochloride, and CI-907, [2S-[1[R*(R*)]], 2 alpha, 3a beta, 7a 7a beta]-1-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino] 1-oxopropyl]octahydro-1H-indole-2-carboxylic acid, monohydrochloride, are two new nonsulfhydryl-type angiotensin-converting enzyme (ACE) inhibitors. Monoester (prodrug) and diacid forms produced concentration-related ACE inhibition in guinea pig serum (IC50 for CI-906 = 8.3 X 10(-9) M, diacid = 2.8 X 10(-9) M; CI-907 = 1.0 X 10(-7) M, diacid = 2.6 X 10(-9) M). In isolated rabbit aortic rings and in in vivo rat and dog autonomic studies, both compounds were highly specific in suppressing the contractile or pressor responses to angiotensin I. In two-kidney, one-clip Goldblatt (renin-dependent) hypertensive rats there was a good correlation between the inhibition of vascular converting enzyme and blood pressure lowering and a poor correlation between blood pressure lowering and plasma and brain converting enzyme inhibition. Cardiovascular, pulmonary, and central nervous system performance evaluations showed no side effects or gross toxicity. The preclinical profile shows CI-906 and CI-907 to be specific, potent, orally active ACE inhibitors. They are expected to have therapeutic utility in hypertension and in any other condition where converting enzyme inhibition would be useful.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Blood Vessels; Captopril; Dipeptides; Dogs; Enalapril; Guinea Pigs; Heart Rate; Hypertension, Renovascular; In Vitro Techniques; Indoles; Isoquinolines; Muscle Contraction; Muscle, Smooth, Vascular; Peptidyl-Dipeptidase A; Quinapril; Rabbits; Rats; Tetrahydroisoquinolines