title: 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.
authors.affiliation: Metabolic and Cardiovascular Diseases, Novartis Institute for Biomedical Research, Summit, NJ 07901, USA. fariborz.firooznia@pharma.novartis.com
authors.forename: Fariborz
authors.initials: F
authors.lastname: Firooznia
authors.forename: Candido
authors.initials: C
authors.lastname: Gude
authors.forename: Kenneth
authors.initials: K
authors.lastname: Chan
authors.forename: Jenny
authors.initials: J
authors.lastname: Tan
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Fink
authors.forename: Paula
authors.initials: P
authors.lastname: Savage
authors.forename: Michael E
authors.initials: ME
authors.lastname: Beil
authors.forename: Charles W
authors.initials: CW
authors.lastname: Bruseo
authors.forename: Angelo J
authors.initials: AJ
authors.lastname: Trapani
authors.forename: Arco Y
authors.initials: AY
authors.lastname: Jeng
mesh_terms: D000147:Acids, Heterocyclic / Q000138:chemical synthesis* / Q000494:pharmacology*; D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008666:Metalloendopeptidases; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology; D011498:Protein Precursors / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000147:Acids, Heterocyclic; D001713:Biphenyl Compounds; C427046:CGS 30084; D019332:Endothelin-1; D016232:Endothelins; D011355:Prodrugs; D011498:Protein Precursors; D013438:Sulfhydryl Compounds; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D000409:Alanine