| Autor: |
Peter C. Isakson, Jerry L. Currie, Ish K. Khanna, A. W. Veenhuizen, Carol M. Koboldt, Yu Yi, Richard M. Weier, Karen Seibert, Paul W. Collins, Julie M. Miyashiro |
| Rok vydání: |
2010 |
| Předmět: |
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| Zdroj: |
ChemInform. 28 |
| ISSN: |
0931-7597 |
| DOI: |
10.1002/chin.199739134 |
| Popis: |
Series of 1,2-diarylpyrroles has been synthesized and found to contain very potent and selective inhibitors of the human cyclooxygenase-2 (COX-2) enzyme. The paper describes short and practical syntheses of the target molecules utilizing the Paal−Knorr reaction. Electrophilic substitution on 1 proceeds in a regioselective fashion, and the method was used to generate a number of tetrasubstituted pyrroles. Detailed SAR on the series has been studied by modifications of the aryl rings and the substituents in the pyrrole ring. Diarylpyrrole 1 is a very potent (COX-2, IC50 = 60 nm) and selective (COX-1/COX-2 = >1700) inhibitor whereas the isomeric 2 is completely inactive against COX-2. Modifications of the substituents on the fluorophenyl ring in 1 yields very potent inhibitors of COX-2 (IC50 = 40−80 nm) with excellent selectivity (1200 to >2500) vs COX-1. Analog 20 containing a sulfonamide group is an excellent inhibitor of COX-2 with an IC50 of 14 nm. Tetrasubstituted pyrroles containing groups such as COCF... |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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