Mercaptoacyl dipeptides were prepared as dual-acting ACEYNEP inhibitors. Inhibition of each enzyme may be explained by different binding models. Structure-activity studies determined that, in this series of compounds, the mercaptopropanoyl dipeptide framework leads to increased affinity for NJZP but diminished ACE activity in vivo. Atrial natriuretic peptide {ANP) is a 28-amino acid peptide hormone that induces diuresis, natriuresis, and vasodilatation.1 ANP is rapidly cleaved and inactivated in vivo, predominantly by the zinc-containing metalloprotease neutral endopeptidase (NEP; EC. 3.4.24. I 1). 2 Inhibitors of NEP potentiate the diuretic, natriuretic, and hypotensive effects of ANP and thus are of potential interest in the treatment of hypertension and congestive heart faihrre (CHQ.3 ~~oten~-conv~g enzyme (ACE) is the ~~ptidyl c~~x~d~e responsible for cleavage of angiotensin I (AI) to the vasoconstrictor octapeptide angiotensin II (AII). ACE inhibitors are widely used for the treatment of hypertension and CHF.4 Several studies have reported that inhibition of ACE augments the vascular and renal effects of both AtW and NESP inhibitors in heart failure suggesting that simultaneous inhibition of both enzymes might prove to be a useful therapeutic approach to Cl-IF.5NEP and ACE have similar mechanisms of proteolytic action. The stmctural requirements of both enzymes allow the design of mercaptoacyl amino acid inhibitors which are selective for either enzyme or active against both.6~7 Captopril(1) is a potent inhibitor of ACE with littIe activity against NEP whereas SQ 28,6038 (2) has the opposite profile. Interestingly, the mercaptoacetyl dipeptide (3a)g has ACE activity comparable to captopril but is >lOOO-times more potent than 1 against NEP. Herein, we present a proposal to rationalize the ACElNEP activities of 3s and disclose preliminary SAR resulting in the discovery of potent inhibitors of both enzymes.