1,2-Diarylpyrroles as potent and selective inhibitors of cyclooxygenase- 2

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 COCF₃, SO₂CF₃, or CH₂OAr at position 3 in the pyrrole ring give excellent inhibitors (COX-2, IC₅₀ = 30-120 nm). In vivo testing in the carrageenan- induced paw edema model in the rat establishes that the 1,2-diarylpyrroles are orally active antiinflammatory agents. Compound 3 is the most potent inhibitor of edema with an ED₅₀ of 4.7 mpk.