DICARBOXYLIC-ACID DIPEPTIDE NEUTRAL ENDOPEPTIDASE INHIBITORS

The synthesis of three series of dicarboxylic acid dipeptide neutral e ndopeptidase 24.11 (NEP) inhibitors is described. In particular, the a mino butyramide 21a exhibited potent NEP inhibitory activity (IC50 = 5 .0 nM) in vitro and in vivo. Blood levels of 21a were determined using an ex vivo method by measuring plasma inhibitory activity in consciou s rats, mongrel dogs, and cynomolgus monkeys. Free drug concentrations were 10-1500 times greater than the inhibitory constant for NEP over the course of a 6 h experiment. A good correlation of free drug concen trations was obtained when comparing values determined by the ex vivo analysis to those calculated from direct HPLC measurements. Plasma atr ial natriuretic factor (exogenous) levels were elevated in rats and do gs after oral administration of 19a. Urinary volume and urinary sodium excretion were also potentiated in anesthetized dogs treated with 21a .