Synthesis and biological activity of novel potent endothelin-converting enzyme-1 inhibitors |
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| Authors: | Firooznia F Gude C Chan K Fink C A Qiao Y Satoh Y Marcopoulos N Savage P Beil M E Bruseo C W Trapani A J Jeng A 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: | Through directed screening of metalloprotease inhibitors, CGS 30084 (1) has been identified as a potent endothelin-converting enzyme-1 (ECE-1) inhibitor in vitro (IC50 = 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. |
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