title: Design and synthesis of potent thiol-based inhibitors of endothelin converting enzyme-1.
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.
authors.affiliation: Metabolic and Cardiovascular Diseases, Novartis Institute for Biomedical Research, Summit, NJ 07901, USA. cynthia.fink@pharma.novartis.com
authors.forename: C A
authors.initials: CA
authors.lastname: Fink
authors.forename: M
authors.initials: M
authors.lastname: Moskal
authors.forename: F
authors.initials: F
authors.lastname: Firooznia
authors.forename: D
authors.initials: D
authors.lastname: Hoyer
authors.forename: D
authors.initials: D
authors.lastname: Symonsbergen
authors.forename: D
authors.initials: D
authors.lastname: Wei
authors.forename: Y
authors.initials: Y
authors.lastname: Qiao
authors.forename: P
authors.initials: P
authors.lastname: Savage
authors.forename: M E
authors.initials: ME
authors.lastname: Beil
authors.forename: A J
authors.initials: AJ
authors.lastname: Trapani
authors.forename: A Y
authors.initials: AY
authors.lastname: Jeng
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D000072396:Endothelin-Converting Enzymes; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes