ABT-963 [2-(3,4-Difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one], a highly potent and selective disubstituted pyridazinone cyclooxgenase-2 inhibitor

被引：42

作者：

Harris, RR ^{[1
]}

Black, L ^{[1
]}

Surapaneni, S ^{[1
]}

Kolasa, T ^{[1
]}

Majest, S ^{[1
]}

Namovic, MT ^{[1
]}

Grayson, G ^{[1
]}

Komater, V ^{[1
]}

Wilcox, D ^{[1
]}

King, L ^{[1
]}

Marsh, K ^{[1
]}

Jarvis, MF ^{[1
]}

Nuss, M ^{[1
]}

Nellans, H ^{[1
]}

Pruesser, L ^{[1
]}

Reinhart, GA ^{[1
]}

Cox, B ^{[1
]}

Jacobson, P ^{[1
]}

Stewart, A ^{[1
]}

Coghlan, M ^{[1
]}

Carter, G ^{[1
]}

Bell, RL ^{[1
]}

机构：

[1] Abbott Labs, Dept R4PM, Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | 2004年 / 311卷 / 03期

关键词：

D O I：

10.1124/jpet.104.070052

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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-methanesulfonylphenyl)- 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 E-2 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.

引用

页码：904 / 912

页数：9

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