Design and Synthesis of Potent, Selective Inhibitors of Endothelin-Converting Enzyme

• Published in: Journal of medicinal chemistry 1998-04, Vol.41 (9), p.1513-1523
• Main Authors: Wallace, Eli M, Moliterni, John A, Moskal, Michael A, Neubert, Alan D, Marcopulos, Nicholas, Stamford, Lisa B, Trapani, Angelo J, Savage, Paula, Chou, Mary, Jeng, Arco Y
• Format: Article
• Language: English
• Subjects: Acetylene - analogs & derivatives; Acetylene - chemical synthesis; Acetylene - chemistry; Acetylene - pharmacology; Amino Acid Sequence; Animals; Aspartic Acid Endopeptidases - antagonists & inhibitors; Biological and medical sciences; Blood Pressure - drug effects; Cardiovascular system; CHO Cells; Cricetinae; Drug Design; Endothelin-1 - antagonists & inhibitors; Endothelin-1 - pharmacology; Endothelin-Converting Enzymes; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Male; Medical sciences; Metalloendopeptidases; Molecular Sequence Data; Neprilysin - antagonists & inhibitors; Organophosphonates - chemical synthesis; Organophosphonates - chemistry; Organophosphonates - pharmacology; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Recombinant Proteins - antagonists & inhibitors; Structure-Activity Relationship; Vasodilator agents. Cerebral vasodilators
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970787c

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]propionic acid (47), an arylacetylene amino phosphonate dipeptide, was found to inhibit ECE-1 and NEP with IC50 values of 14 nM and 2 μM, respectively. Similarly, (S)-[[1-[(2-biphenyl-4-ylethyl)carbamoyl]-4-(2-fluorophenyl)but-3-ynyl]amino]methyl]phosphonic acid (56), an arylacetylene amino phosphonate amide, had IC50's of 33 nM and 6.5 μM 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]amino]-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]amino]-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.