Structural modifications of CGS 26303, a non-peptidic α-aminophosphonate dual ECE/NEP inhibitor lead, were performed to maximize inhibition of recombinant human ECE-1, while maintaining strong NEP inhibition. Specifically, substitution of the α-aminophosphonate moiety with aryl ethyl sidechains led to the discovery of a new class of potent, non-peptidic, dual inhibitors, such as CGS 31447, which blocked ECE-1 and NEP activities with IC50's of 17 and 5 nM, respectively.