title: Novel terphenyls as selective cyclooxygenase-2 inhibitors and orally active anti-inflammatory agents.
abstract: A novel series of terphenyl methyl sulfones and sulfonamides have been shown to be highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. The sulfonamide analogs 17 and 21 were found to be much more potent COX-2 inhibitors and orally active anti-inflammatory agents than the corresponding methyl sulfone analogs 16 and 20, respectively, albeit with some decrease in COX-2 selectivity. Structure-activity relationship studies have determined that incorporation of two fluorine atoms in the central phenyl group, as in 20 and 21, is extremely advantageous for both in vitro COX-2 potency and selectivity as well as in vivo activity. Several noticeable examples in the 1,2-diaryl-4,5-difluorobenzenesulfonamide series are 21a-c,k,l,n (COX-2, IC50 = 0.002-0.004 microM), in which all have in vitro COX-1/COX-2 selectivity > 1000. In addition, sulfonamides 21a,b,d,g,j,m,n,q were shown to have greatly enhanced oral activity with more than 90% inhibition of prostaglandin E2 production in the air pouch model of inflammation. Furthermore, sulfonamide 21b was found to be very active in the rat adjuvant-induced arthritis model (ED50 = 0.05 mg/kg) and carrageenan-induced hyperalgesia assay (ED50 = 38.7 mg/kg) with no indication of gastrointestinal toxicity in rats at doses as high as 200 mg/kg.
authors.affiliation: Searle Research and Development, Monsanto Company, St. Louis, Missouri 63198, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Li
authors.forename: M B
authors.initials: MB
authors.lastname: Norton
authors.forename: E J
authors.initials: EJ
authors.lastname: Reinhard
authors.forename: G D
authors.initials: GD
authors.lastname: Anderson
authors.forename: S A
authors.initials: SA
authors.lastname: Gregory
authors.forename: P C
authors.initials: PC
authors.lastname: Isakson
authors.forename: C M
authors.initials: CM
authors.lastname: Koboldt
authors.forename: J L
authors.initials: JL
authors.lastname: Masferrer
authors.forename: W E
authors.initials: WE
authors.lastname: Perkins
authors.forename: K
authors.initials: K
authors.lastname: Seibert
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: B S
authors.initials: BS
authors.lastname: Zweifel
authors.forename: D B
authors.initials: DB
authors.lastname: Reitz
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007527:Isoenzymes / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects*; D051381:Rats; D013730:Terphenyl Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D013730:Terphenyl Compounds; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases