Angiotensin converting enzyme inhibitors. 10. Aryl sulfonamide substituted N-[1-carboxy-3-phenylpropyl]-L-alanyl-L-proline derivatives as novel antihypertensives

• Published in: Journal of medicinal chemistry Vol. 33; no. 6; pp. 1606 - 1615
• Main Authors: Mencel, James J, Regan, John R, Barton, Jeffrey, Menard, Paul R, Bruno, Joseph G, Calvo, Raul R, Kornberg, Brian E, Schwab, Alfred, Neiss, Edward S, Suh, John T
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.06.1990
• Subjects: Angiotensin-Converting Enzyme Inhibitors - chemical synthesis; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Antihypertensive Agents - chemical synthesis; antihypertensives; Benzothiadiazines; Dipeptides - chemical synthesis; Dipeptides - pharmacology; Diuretics; Drug Design; Enalaprilat - analogs & derivatives; Male; N-(1-carboxy-3-phenylpropyl)-L-alanyl-L-proline; Rats; Sodium Chloride Symporter Inhibitors - chemical synthesis; Sodium Chloride Symporter Inhibitors - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00168a013

Compounds 1a-g consisting of enalaprilat covalently bonded to aryl sulfonamides, including several known thiazide diuretics, were synthesized and tested for ACE inhibitory and diuretic and overall antihypertensive effects. All compounds were potent ACE inhibitors in vitro, with IC50 = 6.5-85 nM. At 10 mg/kg iv or ip in the rat, 1a-g inhibited the AI pressor response by 76-100%; inhibition declined significantly upon oral dosing. Compounds 1a and 1f at 100 mg/kg ip in the sodium-depleted, spontaneously hypertensive rats reduced blood pressure 28-35% and 41-42%, respectively. Compounds 1a and 1f elicited natriuresis and kaliuresis without accompanying volume increases in the rat; 1c at 25 mg/kg iv induced delayed diuresis. Compound 1f has been chosen for further development.