Cardiovascular and antihypertensive activities of the novel non-sulfhydryl converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498).
The cardiovascular and antihypertensive activities of the novel orally active non-sulfhydryl converting enzyme (CE) inhibitor 2-[N-[(S)-1-Ethoxycarbonyl-3-phenyl-propyl]-L-alanyl] -(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) were evaluated in several experimental preparations. The hemodynamic profile of Hoe 498 in anesthetized animals was characterized by a reduction in systemic blood pressure which was associated with a decrease in total peripheral and renal vascular resistance. These effects were enhanced upon sodium depletion. In conscious normotensive rats a single oral administration of Hoe 498 reduced systemic blood pressure for more than 5 h. The development of acute renovascular hypertension in anesthetized rats was prevented by oral pretreatment with Hoe 498. In conscious rats with renovascular hypertension (two-kidney, one clip) single oral doses of Hoe 498 induced a long lasting antihypertensive effect. Chronic oral treatment of spontaneously hypertensive rats with Hoe 498 lowered arterial blood pressure more effectively than enalapril. The threshold antihypertensive dose for Hoe 498 was 0.01 mg/kg/d, for enalapril 1 mg/kg/d. In conscious hypertensive dogs (two-kidney, two wrapped) Hoe 498 at a single oral dose of 10 mg/kg reduced systemic blood pressure for more than 6 h. Oral administration of Hoe 498 in a dose of 1 mg/kg/d for 5 d normalized systemic blood pressure in conscious hypertensive dogs. These findings demonstrate that in various models of experimental hypertension the novel orally active converting enzyme inhibitor Hoe 498 exerts marked cardiovascular and potent prolonged antihypertensive activities, which merit exploration with respect to possible therapeutic benefits.
D000758:Anesthesia; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D006978:Hypertension, Renovascular / Q000503:physiopathology; D008297:Male; D017257:Ramipril; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D012079:Renal Circulation / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000494:pharmacology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D013438:Sulfhydryl Compounds; D017257:Ramipril