This report describes the initial findings of a program focused on the design and synthesis of inhibitors of a putative metalloprotease endothelin converting enzyme (ECE) partially purified from rabbit lung, and the investigation of the effect of the electronic nature of phosphorus on inhibitor potency. Phosphorus-containing ECE inhibitors (phosphonamide, phosphoramide, phosphonate, and phosphinate analogs of phosphoramidon) were synthesized by modifying the rhamnose moiety with simple alkyl groups. Key results: Replacing the rhamnose moiety in phosphoramidon with an ethoxy group yielded inhibitor 16 (IC50 = 109 μM), which was less potent than phosphoramidon but synthetically more attractive. Propyl phosphonamide 17 showed in vitro potency similar to phosphoramidon (IC50 identical) but was 6 times more potent in vivo. The relative potency of analogs varied with phosphorus oxidation state and substituents, where hydrophobic or steric interactions with the enzyme might have masked the electronic effects of phosphorus. Future work will aim to understand these trends and develop structure-activity relationships (SAR) for ECE inhibition.