Design, synthesis, and anti-inflammatory evaluation of a series of novel amino acid-binding 1,5-diarylpyrazole derivatives
文献类型：期刊论文
| 作者 | Minghui Li; Linlin Yin; Maojun Cai; Weiyu Zhang; Yue Huang; Xin Wang ; Xingzu Zhu; Jingkang Shen
|
| 刊名 | 中国药理学报：英文版
 |
| 出版日期 | 2005 |
| 卷号 | 26.0期号:007页码:865 |
| 关键词 | 炎症反应 氨基酸化物1 吡唑派生物 药物治疗 |
| ISSN号 | 1671-4083 |
| 英文摘要 | Aim: To design and synthesize a series of novel amino acid-binding 1,5-diarylpyrazole derivatives, which are intended to act as prodrugs with better aqueous solubility than celecoxib, and which will exert potent anti-inflammatory activi-ties after being converted to their parent compounds in vivo. Methods: To introduce an amino acid, celecoxib analogs containing amino or methylamino group were synthesized first through multi-step chemical reactions. All the synthesized compounds were screened in an intact cell-based assay in vitro and in carrageenan-induced mouse paw edema in vivo. Some active compounds were selected for further evaluation in a carrageenan-induced rat paw edema model. The preliminary pharmacokinetics experiments were conducted using high performance liquid chromatography/mass spectrometry (HPLC/MS). Results: Celecoxib, 6 of the 1,5-diarylpyrazole class of celecoxib analogs, and their amino acid derivatives (hydrochloride salts) were synthesized. In vitro screening, the hydrochloride salts showed decreased inhibitory effects on cyclooxygenase (COX)- 1 and COX-2 compared with their parent compounds, but some exhibited potent anti-inflammatory activity in vivo. Compound 4a was selected for further evaluation, and its anti-inflammatory effect was equivalent to that of celecoxib after oral administration in the carrageenan-induced rat paw edema model. At three doses (25 mg/kg, 50 mg/kg, and 100 mg/kg) the percentage inhibition on edema was 20.7%, 52.6%, and 62.6% (for compound 4a) and 27.8%, 38.4%, and 40.1% (for celecoxib), respectively. Preliminary pharmacokinetic evaluations support the hypothesis that compound 4a was actually converted to its parent compound, compound 4. Conclusion: The compound bound with amino acid acts like prodrug, which can exert anti-inflammatory effect similar to celecoxib after being converted to its parent compound. This finding will be of great benefit in carrying out structural modifications of prodrug-like selective COX-2 inhibitors. |
| 语种 | 英语 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/293047]  |
| 专题 | 中国科学院上海药物研究所 |
| 作者单位 | 中国科学院上海药物研究所 |
| 推荐引用方式 GB/T 7714 | Minghui Li,Linlin Yin,Maojun Cai,et al. Design, synthesis, and anti-inflammatory evaluation of a series of novel amino acid-binding 1,5-diarylpyrazole derivatives[J]. 中国药理学报：英文版,2005,26.0(007):865. |
| APA | Minghui Li.,Linlin Yin.,Maojun Cai.,Weiyu Zhang.,Yue Huang.,...&Jingkang Shen.(2005).Design, synthesis, and anti-inflammatory evaluation of a series of novel amino acid-binding 1,5-diarylpyrazole derivatives.中国药理学报：英文版,26.0(007),865. |
| MLA | Minghui Li,et al."Design, synthesis, and anti-inflammatory evaluation of a series of novel amino acid-binding 1,5-diarylpyrazole derivatives".中国药理学报：英文版 26.0.007(2005):865. |
入库方式： OAI收割
来源：上海药物研究所
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