Synthesis of potent and highly selective nonguanidine azetidinone inhibitors of human tryptase
| Autor: | Wei Meng, Martin L. Ogletree, Robert Zahler, James C. Sutton, Guohua Zhao, Steven M. Seiler, G. A. Jacobs, Arvind Mathur, Zulan Pi, Treuner Uwe D, Karen S. Hartl, Gregory S. Bisacchi, William A. Slusarchyk, Scott A. Bolton |
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| Rok vydání: | 2004 |
| Předmět: |
Proteases
Serine Proteinase Inhibitors Stereochemistry education Clinical Biochemistry Pharmaceutical Science Tryptase Biochemistry Serine chemistry.chemical_compound Drug Discovery medicine Humans Guanidine Molecular Biology chemistry.chemical_classification biology Serine Endopeptidases Organic Chemistry Trypsin Enzyme chemistry Enzyme inhibitor biology.protein Azetidines Molecular Medicine Tryptases medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 14:2227-2231 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2004.02.011 |
| Popis: | Azetidinones such as BMS-363131 (2) and BMS-363130 (3), which contain a guanidine group in the C-3 side chain were previously shown to be very potent inhibitors of human tryptase with high selectivity versus other serine proteases, including trypsin. In this letter, we describe the discovery of a number of potent azetidinone tryptase inhibitors in which the guanidine moiety at the ring C-3 position is replaced with primary or secondary amine or aminopyridine functionality. In particular, BMS-354326 (4) is a highly potent tryptase inhibitor (IC(50)=1.8 nM), which has excellent selectivity against trypsin and most other related serine proteases. |
| Databáze: | OpenAIRE |
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