OPTIMAL RECOGNITION OF NEUTRAL ENDOPEPTIDASE AND ANGIOTENSIN-CONVERTING ENZYME ACTIVE-SITES BY MERCAPTOACYLDIPEPTIDES AS A MEANS TO DESIGN POTENT DUAL INHIBITORS

An interesting approach for the treatment of congestive heart failure and chronic hypertension could be to avoid the formation of angiotensi n II by inhibiting angiotensin converting enzyme (ACE) and to protect atrial natriuretic factor by blocking neutral endopeptidase 24.11 (NEP ). This is support-ed by recent results obtained with potent dual inhi bitors of the two zinc metallopeptidases, such as RE 105, HSCH2CH(CH3) PhCONHCH(CH3)COOH (Fournie-Zaluski et rrl. Proc, Natl. Acad. Sci. U.S. A, 1994, 91, 4072-4076), which reduces blood pressure in experimental models of hypertension, independently of the stilt and renin angiotens in system status, In order to develop new dual inhibitors with improve d affinities, long duration of action, and/or better bioavailabilities , various series of mercaptoacyldipeptides corresponding to the genera l formula HSCH(R(1))CONHCH(R(1)')CON(R)CH(R(2)')COOH have been si synt hesized. The introduction of well-selected beta-branched chains in pos itions R(1) and R(1)', associated with a tyrosine or a cyclic amino ac id in the C-terminal position, led to potent dual inhibitors of NEP an d ACE; such as 21 [N-[(2S)-2-mercapto-3-methylbutanoyl]-Ile-Try] and 2 2 [N-[(2S)-2-mercapto-3-phenylpropanoyl]Ala-Pro] which have IC50 value s in the nanomolar range for NEP and subnanomolar range for ACE, These compounds could have different modes of binding to the two peptidases . In NEP, the dual inhibitors seem to interact only with the S-1' and S-2' subsites, whereas additional interactions with the Si binding sub site of ACE probably account fbr their subnanomolar inhibitory potenci es for this enzyme. The localization of the Pro residue of 22 outside the NEP active site is supported by biochemical data using (Arg(102),G lu)NEP and molecular modeling studies with thermolysin used as model o f WE:P. One hour after oral administration in mice of a single dose (2 .7 x 10(-5) mol/kg, 21 inhibited 80% and 36% of kidney NEP and lung AC E, respectively, while 22 inhibited 40% of kidney NEP and 56% of lung ACE.