Synthesis and Biological Activity of Potent Heterocyclic Thiol-Based Inhibitors of Endothelin-Converting Enzyme-1.

Abstract Directed screening of metalloprotease inhibitors identified CGS 30084 ( 1 ) as a potent inhibitor of endothelin-converting enzyme-1 (ECE-1) in vitro (IC 50 =77 nM). Herein we report the syntheses and biological activities of analogues containing modified biphenyl moieties, bearing heterocyclic proximal rings. Compound 20 , the thioacetate ethyl ester prodrug derivative of compound 19a , was found to be an orally active and potent inhibitor of ECE-1 activity in rats.