Design and synthesis of potent, selective inhibitors of endothelin-converting enzyme

Journal of Medicinal Chemistry
E M WallaceA Y Jeng

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 d...Continue Reading

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Citations

Aug 13, 2013·Journal of Chromatography. a·Andrea F G GarganoMichael Lämmerhofer
Sep 15, 2000·Bioorganic & Medicinal Chemistry Letters·C A FinkA Y Jeng
Feb 24, 2001·Bioorganic & Medicinal Chemistry Letters·F FiroozniaA Y Jeng
Jan 5, 1999·Bioorganic & Medicinal Chemistry Letters·M A MassaA Doherty
Mar 17, 1999·British Journal of Pharmacology·F D Russell, A P Davenport
Jan 12, 2017·Expert Opinion on Therapeutic Patents·Gregory D CunySoumya S Ray
Sep 6, 2005·Bioorganic & Medicinal Chemistry·Yanming DuAllen B Reitz
Mar 11, 2004·The Journal of Peptide Research : Official Journal of the American Peptide Society·N InguimbertB-P Roques
Sep 8, 2000·Journal of Cardiovascular Pharmacology·B M Löffler
Oct 10, 2002·Bioorganic & Medicinal Chemistry Letters·Fariborz FiroozniaArco Y Jeng
Sep 24, 2013·The Journal of Organic Chemistry·Andrea F G GarganoMichael Lämmerhofer
Dec 31, 2004·The Journal of Organic Chemistry·Bart Vanderhoydonck, Christian V Stevens

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