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	Design, synthesis, and anti-inflammatory evaluation of a series of novel amino acid-binding 1,5-diarylpvrazole derivatives
	Li, MH; Yin, LL; Cai, MJ; Zhang, WY; Huang, Y; Wang, X; Zhu, XZ; Shen, JK
刊名	Acta pharmacologica sinica
	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
出版者	BLACKWELL PUBLISHING
WOS记录号	WOS:000230442400014
内容类型	期刊论文
URI标识	http://www.corc.org.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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