Design, synthesis, and anti-inflammatory evaluation of a series of novel amino acid-binding 1,5-diarylpvrazole derivatives
文献类型：期刊论文
| 作者 | Li, MH; Yin, LL; Cai, MJ; Zhang, WY; Huang, Y; Wang, X ; Zhu, XZ; Shen, JK
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| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2005-07 |
| 卷号 | 26期号:7页码:865-872 |
| 关键词 | nonsteroidal anti-inflammatory agents cyclo oxygenase inhibitors celecoxib pyrazole sulfonamide prodrugs |
| ISSN号 | 1671-4083 |
| DOI | 10.1111/j.1745-7254.2005.00151.x |
| 文献子类 | Article |
| 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 activities 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. |
| WOS关键词 | CYCLOOXYGENASE-2 COX-2 INHIBITORS ; BIOLOGICAL EVALUATION ; CELECOXIB ; PHARMACOKINETICS ; PHARMACOPHORE ; EXPRESSION ; PYRAZOLES ; TOXICITY ; ANALOGS |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:2208860 |
| WOS记录号 | WOS:000230442400014 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/273838]  |
| 专题 | 药理学第二研究室 中科院受体结构与功能重点实验室 信息中心 新药研究国家重点实验室 药物化学研究室 |
| 通讯作者 | Shen, JK |
| 作者单位 | Chinese Acad Sci, Grad Sch, Shanghai Inst Biol Sci, Shanghai Inst Mat Med,State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, MH,Yin, LL,Cai, MJ,et al. Design, synthesis, and anti-inflammatory evaluation of a series of novel amino acid-binding 1,5-diarylpvrazole derivatives[J]. ACTA PHARMACOLOGICA SINICA,2005,26(7):865-872. |
| APA | Li, MH.,Yin, LL.,Cai, MJ.,Zhang, WY.,Huang, Y.,...&Shen, JK.(2005).Design, synthesis, and anti-inflammatory evaluation of a series of novel amino acid-binding 1,5-diarylpvrazole derivatives.ACTA PHARMACOLOGICA SINICA,26(7),865-872. |
| MLA | Li, MH,et al."Design, synthesis, and anti-inflammatory evaluation of a series of novel amino acid-binding 1,5-diarylpvrazole derivatives".ACTA PHARMACOLOGICA SINICA 26.7(2005):865-872. |
入库方式： OAI收割
来源：上海药物研究所
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