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 |
| 刊名 | Acta pharmacologica sinica
 |
| 出版日期 | 2005-07-01 |
| 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 |
| 通讯作者 | Shen, jk() |
| 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 |
| WOS类目 | Chemistry, Multidisciplinary ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000230442400014 |
| 出版者 | BLACKWELL PUBLISHING |
| URI标识 | http://www.irgrid.ac.cn/handle/1471x/2378109 |
| 专题 | 中国科学院大学 |
| 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. |
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来源：中国科学院大学
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