DESIGN AND SYNTHESIS OF AN ORALLY-ACTIVE MACROCYCLIC NEUTRAL ENDOPEPTIDASE-24.11 INHIBITOR

A potent macrocyclic inhibitor of neutral endopeptidase (NEP) 24.11 wa s designed using a computer model of the active site of thermolysin. T his 10-membered ring lactam represents a general mimic for any hydroph obic dipeptide in which the two amino acid side chains bind to an enzy me in a contiguous orientation. The parent 10-membered ring lactam was synthesized and exhibited excellent potency as an NEP 24.11 inhibitor (IC50 = 3 nM). In order to improve oral bioavailability, various func tionality was attached to the macrocycle. These modifications lead to CGS 25155, an orally active NEP 24.11 inhibitor that slows down the de gradation of the cardiac hormone atrial natriuretic factor, producing a lowering of blood pressure in the DOCA-salt rat model of hypertensio n.