| Abstract
| - Series of 1,2-diarylpyrroles has been synthesized andfound to contain very potent and selectiveinhibitors of the human cyclooxygenase-2 (COX-2) enzyme. The paperdescribes short andpractical syntheses of the target molecules utilizing the Paal−Knorrreaction. Electrophilicsubstitution on 1 proceeds in a regioselective fashion, andthe method was used to generate anumber of tetrasubstituted pyrroles. Detailed SAR on the serieshas been studied bymodifications of the aryl rings and the substituents in the pyrrolering. Diarylpyrrole 1 is avery potent (COX-2, IC50 = 60 nm) and selective(COX-1/COX-2 = >1700) inhibitor whereasthe isomeric 2 is completely inactive against COX-2.Modifications of the substituents on thefluorophenyl ring in 1 yields very potent inhibitors ofCOX-2 (IC50 = 40−80 nm) with excellentselectivity (1200 to >2500) vs COX-1. Analog20 containing a sulfonamide group is anexcellentinhibitor of COX-2 with an IC50 of 14 nm.Tetrasubstituted pyrroles containing groups suchas COCF3, SO2CF3, orCH2OAr at position 3 in the pyrrole ring giveexcellent inhibitors (COX-2, IC50 = 30−120 nm). In vivo testing inthe carrageenan-induced paw edema model in therat establishes that the 1,2-diarylpyrroles are orally activeantiinflammatory agents. Compound3 is the most potent inhibitor of edema with anED50 of 4.7 mpk.
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