TY - JOUR T1 - ABT-963 [2-(3,4-Difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2<em>H</em>-pyridazin-3-one], A Highly Potent and Selective Disubstituted Pyridazinone Cyclooxgenase-2 Inhibitor JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 904 LP - 912 DO - 10.1124/jpet.104.070052 VL - 311 IS - 3 AU - Richard R. Harris AU - Lawrence Black AU - Sekhar Surapaneni AU - Teodozyj Kolasa AU - Sandra Majest AU - Marian T. Namovic AU - George Grayson AU - Victoria Komater AU - Denise Wilcox AU - Linda King AU - Kennan Marsh AU - Michael F. Jarvis AU - Merrill Nuss AU - Hugh Nellans AU - Lee Pruesser AU - Glenn A. Reinhart AU - Bryan Cox AU - Peer Jacobson AU - Andrew Stewart AU - Michael Coghlan AU - George Carter AU - Randy L. Bell Y1 - 2004/12/01 UR - http://jpet.aspetjournals.org/content/311/3/904.abstract N2 - Nonsteriodal anti-inflammatory drugs (NSAIDs) are efficacious for the treatment of pain associated with inflammatory disease. Clinical experience with marketed selective cyclooxygenase-2 (COX-2) inhibitors (celecoxib, rofecoxib, and valdecoxib) has confirmed the utility of these agents in the treatment of inflammatory pain with an improved gastrointestinal safety profile relative to NSAID comparators. These COX-2 inhibitors belong to the same structural class. Each contains a core heterocyclic ring with two appropriately substituted phenyl rings appended to adjacent atoms. Here, we report the identification of vicinally disubstituted pyridazinones as potent and selective COX-2 inhibitors. The lead compound in the series, ABT-963 [2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one], has excellent selectivity (ratio of 276, COX-2/COX-1) in human whole blood, improved aqueous solubility compared with celecoxib and rofecoxib, high oral anti-inflammatory potency in vivo, and gastric safety in the animal studies. After oral administration, ABT-963 reduced prostaglandin E2 production in the rat carrageenan air pouch model (ED50 of 0.4 mg/kg) and reduced the edema in the carrageenan induced paw edema model with an ED30 of 1.9 mg/kg. ABT-963 dose dependently reduced nociception in the carrageenan hyperalgesia model (ED50 of 3.1 mg/kg). After 14 days of dosing in the adjuvant arthritis model, ABT-963 had an ED50 of 1.0 mg/kg in reducing the swelling of the hind paws. Magnetic resonance imaging examination of the diseased paws in the adjuvant model showed that ABT-963 significantly reduced bone loss and soft tissue destruction. ABT-963 is a highly selective COX-2 inhibitor that may have utility in the treatment of the pain and inflammation associated with arthritis. The American Society for Pharmacology and Experimental Therapeutics ER -