Abstract
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.
Footnotes
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doi:10.1124/jpet.104.070052.
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ABBREVIATIONS: COX, cyclooxygenase; A23187, calcimycin; HPLC, high-performance liquid chromatography; ELISA, enzyme-linked immunosorbent assay; TXB2, thromboxane B2; LPS, lipopolysaccharide; PGE2, prostaglandin E2; IL, interleukin; MRI, magnetic resonance imaging; CNS, central nervous system; PEG-400, polyethylene glycol-400; MAP, mean arterial pressure; DuP-697, 2-bromo-4-(4′-sulfonylmethyl)phenyl-5-(4′-fluoro)phenylthiophene; ABT-963, 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one; A-241611, 2,4-bis-(4-fluoro-phenyl)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-one; A-282904, 4-[1-3,4-difluoro-phenyl)-5-isobutoxy-6-oxo-1,6-dihydro-pyridazin-4-yl]-benzenesulfonamide.
- Received May 7, 2004.
- Accepted July 23, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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