Inhibitors of the zinc protease neutral endopeptidase (NEP, EC 3.4. 24.11) offer significant therapeutic interest as antihypertensives due to their ability to potentiate the biological action of the circulating natriuretic hormone ANF (atrial natriuretic factor). N-Phosphonomethyl dipeptides bearing a central (4-phenyl) phenylalanine residue have been designed to exert potent and selective NEP inhibition. In particular,(S)-3-[N-[2-[(phosphonomethyl) amino]-3-(4-biphenylyl) propionyl] amino] propionic acid (10a)(CGS 24592) displayed high inhibitory potency in vitro (IC50= 1.9±0.1 nM) and a long plasma half-life in rats but lacked oralbioavailability. This drawback was overcome by using esterase-sensitive (acyloxy) alkyl phosphonates. More remarkable, several diaryl phosphonate derivatives of 10a also performed as effective prodrugs. Specifically, the structurally simple diphenyl phosphonate 18 (CGS 25462) induced potent inhibition of NEP ex vivo for at least 8 h after oral administration to rats (30 mg/kg). Its antihypertensive effect was demonstrated in DOCA-salt rats. At 30 mg/kg orally, 18 caused a significant reduction in mean arterial pressure measuring-35±7 mmHg at 5-h postdosing. The a-aminomethyl phosphonate 18 represents a new generation of selective NEP inhibitors that combine high potency, long durationof action, and oral bioavailability. Therefore, it holds promise as a novel therapeutic agent for the treatment of human hypertension and congestive heart failure.