Design and synthesis of potent thiol-based inhibitors of endothelin converting enzyme-1 |
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Authors: | Fink C A Moskal M Firooznia F Hoyer D Symonsbergen D Wei D Qiao Y Savage P Beil M E Trapani A J Jeng A Y |
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Institution: | Metabolic and Cardiovascular Diseases, Novartis Institute for Biomedical Research, Summit, NJ 07901, USA. cynthia.fink@pharma.novartis.com |
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Abstract: | Through directed screening of compounds prepared as metalloprotease inhibitors a compound, CGS 30084, that had potent endothelin converting enzyme-1 (ECE-1) in vitro inhibitory activity (IC50 = 77 nM) was identified. Herein we report the synthesis and optimization of ECE-1 inhibitory activity of additional analogues from this lead. Compound 3c, the thioacetate methyl ester derivative of compound 4c, was found to be a long acting inhibitor of ECE-1 activity in rats after oral administration. |
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