title: Synthesis and biological activity of novel potent endothelin-converting enzyme-1 inhibitors.
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.
authors.affiliation: Metabolic and Cardiovascular Diseases, Novartis Institute for Biomedical Research, Summit, NJ 07901, USA. fariborz.firooznia@pharma.novartis.com
authors.forename: F
authors.initials: F
authors.lastname: Firooznia
authors.forename: C
authors.initials: C
authors.lastname: Gude
authors.forename: K
authors.initials: K
authors.lastname: Chan
authors.forename: C A
authors.initials: CA
authors.lastname: Fink
authors.forename: Y
authors.initials: Y
authors.lastname: Qiao
authors.forename: Y
authors.initials: Y
authors.lastname: Satoh
authors.forename: N
authors.initials: N
authors.lastname: Marcopoulos
authors.forename: P
authors.initials: P
authors.lastname: Savage
authors.forename: M E
authors.initials: ME
authors.lastname: Beil
authors.forename: C W
authors.initials: CW
authors.lastname: Bruseo
authors.forename: A J
authors.initials: AJ
authors.lastname: Trapani
authors.forename: A Y
authors.initials: AY
authors.lastname: Jeng
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D011355:Prodrugs; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001713:Biphenyl Compounds; C427046:CGS 30084; D004791:Enzyme Inhibitors; D011355:Prodrugs; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D000409:Alanine