A Novel 1,5-Diarylpyrazole Derivative Exerts Its Anti-inflammatory Effect by Inhibition of Cyclooxygenase-2 Activity as a Prodrug

doi:10.1248/bpb.32.1032

	A Novel 1,5-Diarylpyrazole Derivative Exerts Its Anti-inflammatory Effect by Inhibition of Cyclooxygenase-2 Activity as a Prodrug
	Yin, Lin-Lin 1; Li, Ming-Hui 2; Wang, Xin2 ; Zhang, Wei-Yu 2
刊名	BIOLOGICAL & PHARMACEUTICAL BULLETIN
	2009-06
卷号	32 期号:6 页码:1032-1036
关键词	cyclooxygenase-2 inflammation carrageenan-induced paw edema air pouch model prodrug
ISSN号	0918-6158
DOI	10.1248/bpb.32.1032
文献子类	Article
英文摘要	In the present study, we designed and synthesized a novel 1,5-diarylpyrazole derivative, 2-amino-N-(2-methyl-5-(1-(4-sulfamoylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl) acetamide hydrochloride (CC06), which was intended to act as a prodrug and would exert potent anti-inflammatory activity after being converted to its parent compound in vivo. In vitro cell-based biological assay, CC06 showed decreased inhibitory effects on cyclooxygenase (COX)-1 and COX-2 compared with its parent compounds, but it exhibited potent anti-inflammatory activity in vivo. The anti-inflammatory effect was evaluated in a carrageenan-induced rat paw edema model and CC06 (15, 30, 60 mg/kg, intragastrically) reduced rat paw edema in a dose-dependent manner. CC06 is also a selective inhibitor of COX-2 since it can reduce prostaglandin E-2 (PGE(2)) production in the inflamed pouch dose-dependently without affecting PGE(2) production in stomach in rat air pouch model. Furthermore, preliminary pharmacokinetics experiments were conducted using high performance liquid chromatography/mass spectrometry (HPLU/MS) to detect whether CC06 can convert to its parent compound or not. Our results supported the hypothesis that CC06 was actually converted to its parent compound. These suggested that CC06 served as an anti-inflammatory prodrug and actually converted to its parent compound to exert its anti-inflammatory effect. This finding will be of great benefit in carrying out structural modifications of prodrug-like selective COX-2 inhibitors.
资助项目	Ministry of Sciences and Technology of China[2004CB720305]
WOS关键词	SELECTIVE-INHIBITION ; MESSENGER-RNA ; CELECOXIB ; INFLAMMATION ; EXPRESSION ; RAT ; PYRAZOLES ; SYNTHASE ; DESIGN ; ENZYME
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	PHARMACEUTICAL SOC JAPAN
WOS记录号	WOS:000266483500013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279221]
专题	信息中心药物化学研究室
通讯作者	Yin, Lin-Lin
作者单位	1.Capital Med Univ, Xuanwu Hosp, Dept Pharmacol, Beijing 100053, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Yin, Lin-Lin,Li, Ming-Hui,Wang, Xin,et al. A Novel 1,5-Diarylpyrazole Derivative Exerts Its Anti-inflammatory Effect by Inhibition of Cyclooxygenase-2 Activity as a Prodrug[J]. BIOLOGICAL & PHARMACEUTICAL BULLETIN,2009,32(6):1032-1036.
APA	Yin, Lin-Lin,Li, Ming-Hui,Wang, Xin,&Zhang, Wei-Yu.(2009).A Novel 1,5-Diarylpyrazole Derivative Exerts Its Anti-inflammatory Effect by Inhibition of Cyclooxygenase-2 Activity as a Prodrug.BIOLOGICAL & PHARMACEUTICAL BULLETIN,32(6),1032-1036.
MLA	Yin, Lin-Lin,et al."A Novel 1,5-Diarylpyrazole Derivative Exerts Its Anti-inflammatory Effect by Inhibition of Cyclooxygenase-2 Activity as a Prodrug".BIOLOGICAL & PHARMACEUTICAL BULLETIN 32.6(2009):1032-1036.