Propyphenazone-Based Analogues as Prodrugs and Selective Cyclooxygenase-2 Inhibitors
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- 作者：Mohamed F. Radwan ; Kevin N. Dalby ; Tamer S. Kaoud
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2014
- 出版时间：September 11, 2014
- 年：2014
- 卷：5
- 期：9
- 页码：983-988
- 全文大小：364K
- ISSN：1948-5875
文摘
Improving the gastrointestinal safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) is an important goal. Herein, we report two strategies, using the nonacidic propyphenazone structure, with potential to overcome the side effects of NSAIDs. Propyphenazone was employed to temporarily mask the free acid group of the widely used NSAIDs ibuprofen, diclofenac, and ketoprofen to develop three mutual prodrugs hypothesized to have minimal GI irritation. The three prodrugs exhibit in vivo anti-inflammatory and analgesic activities with improved potency over each parent drug when compared to a nonhydrolyzable control betahistine鈥損ropyphenazone (BET鈥揗P). Additionally, ANT鈥揗P formed by the irreversible coupling of propyphenazone and 4-aminoantipyrine, displayed exceptional COXII selectivity (COXII IC50 of 0.97 卤 0.04 渭M, compared to no observed inhibition of COXI at 160 渭M). Inhibition of COXII suppresses inflammatory diseases without affecting COXI-mediated GI tract events. ANT鈥揗P exhibited maximal analgesic effect when tested in vivo in an abdominal writhing assay (100% protection) and its anti-inflammatory activity showed a peak at 2 h in a carrageenan-induced paw edema model. Its unique selectivity toward the COXII enzyme was investigated using molecular modeling techniques.