Synthesis and biological activity of potent heterocyclic thiol-based inhibitors of endothelin-converting enzyme-1 |
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| Authors: | Firooznia Fariborz Gude Candido Chan Kenneth Tan Jenny Fink Cynthia A Savage Paula Beil Michael E Bruseo Charles W Trapani Angelo J Jeng Arco Y |
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| Affiliation: | Metabolic and Cardiovascular Diseases, Novartis Institute for Biomedical Research, Summit, NJ 07901, USA. fariborz.firooznia@pharma.novartis.com |
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| 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. |
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