title: 1,2-Diarylpyrroles as potent and selective inhibitors of cyclooxygenase-2.
abstract: 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.
authors.affiliation: Searle Research and Development, Skokie, Illinois 60077, USA.
authors.forename: I K
authors.initials: IK
authors.lastname: Khanna
authors.forename: R M
authors.initials: RM
authors.lastname: Weier
authors.forename: Y
authors.initials: Y
authors.lastname: Yu
authors.forename: P W
authors.initials: PW
authors.lastname: Collins
authors.forename: J M
authors.initials: JM
authors.lastname: Miyashiro
authors.forename: C M
authors.initials: CM
authors.lastname: Koboldt
authors.forename: A W
authors.initials: AW
authors.lastname: Veenhuizen
authors.forename: J L
authors.initials: JL
authors.lastname: Currie
authors.forename: K
authors.initials: K
authors.lastname: Seibert
authors.forename: P C
authors.initials: PC
authors.lastname: Isakson
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000627:therapeutic use; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D007527:Isoenzymes; D008565:Membrane Proteins; D015394:Molecular Structure; D011451:Prostaglandin-Endoperoxide Synthases; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D000096926:Benzenesulfonamides
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D011758:Pyrroles; D011994:Recombinant Proteins; D013449:Sulfonamides; C106270:4-(2-(4-fluorophenyl)-1H-pyrrol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; C496513:Ptgs1 protein, rat