DUAL INHIBITION OF ANGIOTENSIN-CONVERTING ENZYME AND NEUTRAL ENDOPEPTIDASE - A NEW WAY IN THE FIELD OF HYPERTENSION

Two metallopeptidases, angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) are involved respectively in the release of angiotensine II which is a vasoconstrictor, and in the metabolism of atrial natriuretic peptide which is diuretic and bradykinin which is a vasodilatator. The dual inhibition of these two peptidases represents a new way to regulate the blood pressure in various cardiovascular Taking into account the mechanism of action of metallopeptidases and the substrate specificity of ACE and NEP, dual inhibitors corresponding to the general formula HS-CH2-CH(R1)CONH-CH(R2)COOH and HS-CH(R1)CONH-CH(R2)CONH-CH(R3)COOH and having inhibitory potencies on each enzyme in the nanomolar range were designed. The most efficient inhibitors have been transformed into lypophilic prodrugs which were found to be active after oral administration. These compounds have been tested on an experimental model of hypertension in rats and, as expected, have been shown to be both diuretic (NEP inhibition) and hypotensive (ACE inhibition).