Pharmacological properties of the new orally active angiotensin 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).
2-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S) - 2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) can be characterized as a novel orally active non-sulfhydryl containing angiotensin converting enzyme inhibitor. Designed as a prodrug to improve the bioavailability Hoe 498 has to be deesterified to its active moiety Hoe 498-diacid to develop full inhibitory potency. The present study compares the basic pharmacological properties of Hoe 498 in rats and dogs to those of enalapril. In vitro assays revealed equal potency of both Hoe 498-diacid and enalaprilat. In vivo the inhibitory potency was judged by the ability to attenuate the pressor response induced by angiotensin I. The results indicate that Hoe 498 was approximately 10 times more potent than enalapril after oral intake in conscious rats or after intraduodenal administration in anaesthetized rats, whereas after intravenous injection both compounds exhibited equal potency. Hoe 498 was at least twice as potent as enalapril after oral or intraduodenal administration in dogs but about 4 times more potent than enalapril after intravenous injection. In conclusion, the obtained data point to a prodrug pathway for Hoe 498 which should be advantageous with regard to bioavailability, onset and duration of action and therefore promises to be favourable in the treatment of different cardiovascular diseases.
D000803:Angiotensin I / Q000037:antagonists & inhibitors; 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*; D002216:Captopril / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004285:Dogs; D004656:Enalapril; D008297:Male; D017257:Ramipril; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D000806:Angiotensin-Converting Enzyme Inhibitors; D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D004151:Dipeptides; D004656:Enalapril; D000803:Angiotensin I; D002216:Captopril; D017257:Ramipril