Synthesis and biological evaluation of isoxazolo[4,5-d]pyridazin-4-(5H)-one analogues as potent anti-inflammatory agents

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• 作者：Keriman Ö ; zadal谋^a ; ^b ; Fü ; gen Ö ; zkanl谋^a ; Sarthak Jain^b ; Praveen P.N. Rao^c ; Carlos A. Velá ; zquez-Martí ; nez^b ; ^{cvelazquez@pharmacy.ualberta.ca}
• 关键词：Cyclooxygenase ; Lipoxygenase ; Isoxazolo[4 ; 5-d]pyridazin-4-(5H)-one ; NSAID ; Docking
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：1 May, 2012
• 卷：20
• 期：9
• 页码：2912-2922
• 文件大小：667 K

摘要

In this study, eighteen new isoxazolo[4,5-d]pyridazin-4(5H)-one derivatives possessing either a 1,3,4-thiadiazole or a 1,2,4-triazole-5-thione moiety were synthesized and tested for anti-inflammatory activity in vitro (COX-1/COX-2, 5-LOX) and in vivo (rat paw edema assay). Compounds 15, 16, 25, 26 and 28-30 showed dual COX-2 (IC₅₀鈥檚 in the 2.1-10.9 渭M range), and 5-LOX (IC₅₀鈥檚 in the 6.3-63.5 渭M range) inhibitory activity. When administered orally to rats, dual COX-2/5-LOX inhibitors showed higher anti-inflammatory activity in vivo (30-45%reduction of the inflammatory response) than the reference drug ibuprofen (18%). Among dual COX-2/5-LOX inhibitors, the most potent compound (28) exhibited the best anti-inflammatory profile by inhibiting both COX-2 (IC₅₀ = 2.1 渭M) and 5-LOX (IC₅₀ = 6.3 渭M) enzymes. We investigated the binding interactions of compound 28 by an enzyme-ligand molecular modeling (docking) studies, which showed favorable binding interactions in both COX-2 and 5-LOX active sites. Furthermore, the dual acting COX-2/5-LOX compound 28 exhibited a superior gastrointestinal safety profile (ulcer index = 0.25) compared to the reference drug ibuprofen (UI = 7.0) when administered orally at the same molar dose. These observations suggest that isoxazolo[4,5-d]pyridazin-4(5H)-one analogs represent a new scaffold to design potent, effective, and safe anti-inflammatory agents possessing dual COX-2/5-LOX inhibitory activity.