indolapril-hydrochloride and Hypertension--Renal

A series of non-sulfhydryl modified dipeptides related to CI-906, CI-907, and enalapril was prepared in which various isosteric moieties (O, S, SO, SO2) have been substituted for the amino group and in which the proline residue has been replaced with various hydrophobic amino acids. The compounds were evaluated in vitro for inhibition of angiotensin-converting enzyme and in vivo for antihypertensive activity. Compound 7c, the most potent member of this series, had an in vitro IC50 of 1.4 X 10(-8) M and showed modest oral antihypertensive activity at 30 mg/kg in conscious, two kidney, one clip Goldblatt hypertensive rats. Structure-activity relationships are discussed.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Chemical Phenomena; Chemistry; Dipeptides; Enalapril; Guinea Pigs; Hypertension, Renal; Indoles; Isoquinolines; Quinapril; Rats; Structure-Activity Relationship; Tetrahydroisoquinolines

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