UK-69, 578, a novel inhibitor of EC 3.4.24.11 which increases endogenous ANF levels and is natriuretic and diuretic

A search for potent inhibitors of EC 3.4.24.11, an enzyme which is found most abundantly in the kidney and which degrades atrial natriuretic factor, has led to the identification of UK-69, 578. Structure-activity studies starting from substituted N-carboxymethyl dipeptide inhibitors resulted in the introduction of a cyclo-alkane P 1′ residue and in the replacement of the aza-link between P 1 and P 1′ residues by a methylene group, with a net ten-fold potency gain. UK-69, 578 increases endogenous ANF levels and produces natriuretic and diuretic responses intravenously in mice.