title: Evaluation of COX-1/COX-2 selectivity and potency of a new class of COX-2 inhibitors.
abstract: A new class of selective cyclooxygenase-2 (COX-2) inhibitors has been identified by high throughput screening. Structurally distinct from previously described selective COX-2 inhibitors, these benzopyrans contain a carboxylic acid function and CF3 functionality. The compound SC-75,416 is a representative of this class. A range if in vitro and in vivo tests were employed to characterize its potency and selectivity. Using human recombinant enzymes, this compound displays a concentration that provides 50% inhibition (IC50) of 0.25 microM for COX-2 and 49.6 microM for COX-1. A mutation of the side pocket residues in COX-2 to COX-1 had little effect on potency suggesting that these inhibitors bind in a unique manner in COX-2 distinct from COX-2 inhibiting diaryl heterocycles. Using rheumatoid arthritic synovial cells stimulated with interleukin-1beta (IL-1beta) and washed platelets the compound displayed IC50 of 3 nM and 400 nM respectively. Potency and selectivity was maintained but predictably right shifted in whole blood with IC50 of 1.4 microM for lipopolysaccharide (LPS) stimulated induction of COX-2 and >200 microM for inhibition of platelet thromboxane production. SC-75,416 is 89% bioavailable and its in vivo half life is sufficient for once a day dosing. In the rat air pouch model of inflammation, the compound inhibited PGE2 production with an effective dose that provides 50% inhibition (ED50) of 0.4 mg/kg, while sparing gastric prostaglandin E2 (PGE2) production with an ED50 of 26.5 mg/kg. In a model of acute inflammation and pain caused by carrageenan injection into the rat paw, the compound reduced edema and hyperalgesia with ED50s of 2.7 and 4 mg/kg respectively. In a chronic model of arthritis the compound demonstrated an ED50 of 0.081 mg/kg and an ED(80) of 0.38 mg/kg. In a model of neuropathic pain, SC-75,416 had good efficacy. This compound's unique chemical structure and effect on COX enzyme binding and activity as well as its potency and selectivity may prove useful in treating pain and inflammation.
authors.affiliation: Pfizer Global Research and Development, 700 Chesterfield Village Parkway N., Chesterfield, Missouri 63198, United States. James.k.gierse@pfizer.com
authors.forename: James
authors.initials: J
authors.lastname: Gierse
authors.forename: Maureen
authors.initials: M
authors.lastname: Nickols
authors.forename: Kathleen
authors.initials: K
authors.lastname: Leahy
authors.forename: James
authors.initials: J
authors.lastname: Warner
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Luz
authors.initials: L
authors.lastname: Cortes-Burgos
authors.forename: Jeffery
authors.initials: J
authors.lastname: Carter
authors.forename: Karen
authors.initials: K
authors.lastname: Seibert
authors.forename: Jaime
authors.initials: J
authors.lastname: Masferrer
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000201:enzymology; D001578:Benzopyrans / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D002351:Carrageenan; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D008026:Ligation; D016296:Mutagenesis / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D013127:Spinal Nerves / Q000293:injuries / Q000473:pathology; D013379:Substrate Specificity; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D052246:Cyclooxygenase 2 Inhibitors; D011994:Recombinant Proteins; C529433:SC-75416; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2