Synthesis and biological activity of novel potent endothelin-converting enzyme-1 inhibitors

Abstract Through directed screening of metalloprotease inhibitors, CGS 30084 ( 1 ) has been identified as a potent endothelin-converting enzyme-1 (ECE-1) inhibitor in vitro (IC 50 =77 nM). Herein we report the syntheses and biological activities of analogues derived from this lead, based on modifications of the biphenyl moiety. Compound 10 , the thioacetate methyl ester prodrug derivative of compound 6m , was found to be an orally active and potent inhibitor of ECE-1 activity in rats.