title: Design and synthesis of potent, selective inhibitors of endothelin-converting enzyme.
abstract: Endothelin-1 is the most potent peptidic vasoconstrictor discovered to date. The final step of posttranslational processing of this peptide is the conversion of its precursor by endothelin-converting enzyme-1 (ECE-1), a metalloprotease which displays high amino acid sequence identity with neutral endopeptidase 24.11 (NEP) especially at the catalytic center. A series of potent and selective arylacetylene-containing ECE-1 inhibitors have been prepared. (S, S)-3-Cyclohexyl-2-[[5-(2, 4-difluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]amino] propio nic acid (47), an arylacetylene amino phosphonate dipeptide, was found to inhibit ECE-1 and NEP with IC50 values of 14 nM and 2 microM, respectively. Similarly, (S)-[[1-[(2-biphenyl-4-ylethyl)carbamoyl]-4-(2-fluorophenyl)but-3- yny l]amino]methyl]phosphonic acid (56), an arylacetylene amino phosphonate amide, had IC50's of 33 nM and 6.5 microM for ECE-1 and NEP, respectively. Slight modification of the aryl moiety was found to have dramatic effects on ECE-1/NEP selectivity. The 2-fluoro dipeptide analogue, (S, S)-2-[[5-(2-fluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]+ ++amin o]-4-methylpentanoic acid (40), showed a 72-fold selectivity for ECE-1 over NEP, while the 3-fluoro dipeptide analogue, (S, S)-2-[[5-(3-fluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]+ ++amin o]-4-methylpentanoic acid (22), was equipotent for ECE-1 and NEP. Several of these inhibitors were shown to be potent in blocking ET-1 production in vivo as demonstrated by the big ET-1-induced pressor response in rats. These potent inhibitors are the most selective for ECE-1 reported to date and are envisaged to have a variety of therapeutic applications.
authors.affiliation: Metabolic and Cardiovascular Diseases Research, Novartis Pharmaceuticals Corporation, 556 Morris Avenue, Summit, New Jersey 07901, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Wallace
authors.forename: J A
authors.initials: JA
authors.lastname: Moliterni
authors.forename: M A
authors.initials: MA
authors.lastname: Moskal
authors.forename: A D
authors.initials: AD
authors.lastname: Neubert
authors.forename: N
authors.initials: N
authors.lastname: Marcopulos
authors.forename: L B
authors.initials: LB
authors.lastname: Stamford
authors.forename: A J
authors.initials: AJ
authors.lastname: Trapani
authors.forename: P
authors.initials: P
authors.lastname: Savage
authors.forename: M
authors.initials: M
authors.lastname: Chou
authors.forename: A Y
authors.initials: AY
authors.lastname: Jeng
mesh_terms: D000114:Acetylene / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D015195:Drug Design; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases; D008969:Molecular Sequence Data; D015260:Neprilysin / Q000037:antagonists & inhibitors; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D019332:Endothelin-1; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D011994:Recombinant Proteins; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes; D000114:Acetylene