A series of α-aminophosphonic acid derivatives and a series of phosphoramidate derivatives have been synthesized and evaluated as inhibitors of a phosphoramidon-sensitive metalloproteinase endothelin converting enzyme (ECE). Some of these compounds exhibit potent ECE inhibitory activity. The most potent inhibitor (XIIb), 3-(1-naphthyl)-1-phosphonopropyl-L-leucyl-L-tryptophan, showed an IC50 value of 0.26 μM against ECE and an ECE/NEP selectivity ratio of 540, which is 10-fold more potent in ECE inhibition and 400 times more selective than phosphoramidon. Introduction of a Pl unit (a substituent at the α-position of the aminophosphonic acid moiety) into the inhibitor structures enhanced both ECE inhibitory activity and ECE/NEP selectivity, and this Pl unit is crucial for both potency and selectivity. XIIb is the most potent and selective ECE inhibitor in this series and will be a useful tool for pharmacological studies of ECE.