RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 904
OP 912
DO 10.1124/jpet.104.070052
VO 311
IS 3
A1 Richard R. Harris
A1 Lawrence Black
A1 Sekhar Surapaneni
A1 Teodozyj Kolasa
A1 Sandra Majest
A1 Marian T. Namovic
A1 George Grayson
A1 Victoria Komater
A1 Denise Wilcox
A1 Linda King
A1 Kennan Marsh
A1 Michael F. Jarvis
A1 Merrill Nuss
A1 Hugh Nellans
A1 Lee Pruesser
A1 Glenn A. Reinhart
A1 Bryan Cox
A1 Peer Jacobson
A1 Andrew Stewart
A1 Michael Coghlan
A1 George Carter
A1 Randy L. Bell
YR 2004
UL http://jpet.aspetjournals.org/content/311/3/904.abstract
AB 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