Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels

doi:10.1021/acs.jmedchem.7b00304

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	Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels
	Qu, Chunrong 13,14; Ding, Mingmin 13,14; Zhu, Yingmin 8; Lu, Yungang 8; Du, Juan 7; Miller, Melissa 5,6,15; Tian, Jinbin 8; Zhu, Jinmei 13,14; Xui, Jian 3,4; Wen, Meng 13,14
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2017-06-08
卷号	60 期号:11 页码:4680-4692
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.7b00304
文献子类	Article
英文摘要	Transient receptor potential canonical 3/6/7 (TRPC3/6/7) are highly homologous receptor-operated nonselective cation channels. Despite their physiological significance, very few selective and potent agonists are available for functional examination of these channels. Using a cell-based high throughput screening approach, a lead compound with the pyrazolopyrimidine skeleton was identified as a TRPC6 agonist. Synthetic schemes for the lead and its analogues were established, and structural activity relationship studies were carried out. A series of potent and direct agonists of TRPC3/6/7 channels were identified, and among them, 4m-4p have a potency order of TRPC3 > C7 > C6, with 4n being the most potent with an EC50 of <20 nM on TRPC3. Importantly, these compounds exhibited no stimulatory activity on related TRP channels. The potent and selective compounds described here should be suitable for evaluation of the roles of TRPC channels in the physiology and pathogenesis of diseases, including glomerulosderosis and cancer.
资助项目	NSFC[81573383] ; NSFC[21390402] ; NSFHP[2014CFB704] ; ISTCPC[2015DFA30440] ; ISTCPC[2014cFB30020] ; Applied Basic Research Program of Wuhan Municipal Bureau of Science Technology[00000000] ; Applied Basic Research Programs of Scientific and Technologic Council of Suzhou[SYG201521] ; Natural Science Foundation of Jiangsu Province[BK20160387] ; Beijing Nova Plan Z[131107000413063] ; Fundamental Research Funds for the Central Universities[00000000] ; U.S. National Institutes of Health[NS056942] ; U.S. National Institutes of Health[NS092377] ; U.S. National Institutes of Health[U54 MH084691]
WOS关键词	TRPC6 CHANNELS ; SMALL-MOLECULE ; CARDIAC-HYPERTROPHY ; CATION CHANNEL ; CELLS ; INHIBITORS ; CALCIUM ; DIACYLGLYCEROL ; IDENTIFICATION ; HYPERTENSION
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000404811500013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272612]
专题	神经药理学研究国际科学家工作站
通讯作者	Wang, Hongbo; Zhu, Michael X.; Hong, Xuechuan
作者单位	1.Tibet Univ, Coll Med, Lasa 850000, Tibet, Peoples R China; 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Int Scientist Working Stn Neuropharmacol, Shanghai 201203, Peoples R China; 4.China Pharmaceut Univ, Jiangsu Prov Key Lab TCM Evaluat & Translat Dev, State Key Lab Nat Med, Nanjing 211198, Jiangsu, Peoples R China; 5.Johns Hopkins Univ, Sch Med, Johns Hopkins Ion Channel Ctr, Baltimore, MD 21205 USA; 6.Johns Hopkins Univ, Sch Med, High Throughput Biol Ctr, Dept Neurosci, Baltimore, MD 21205 USA; 7.Anhui Med Univ, Sch Basic Med Sci, Hefei 230032, Anhui Province, Peoples R China; 8.Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USA; 9.Essen Biosci, Ann Arbor, MI 48108 USA; 10.GlaxoSmithKline, Philadelphia, PA 19103 USA;
推荐引用方式 GB/T 7714	Qu, Chunrong,Ding, Mingmin,Zhu, Yingmin,et al. Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017,60(11):4680-4692.
APA	Qu, Chunrong.,Ding, Mingmin.,Zhu, Yingmin.,Lu, Yungang.,Du, Juan.,...&Hong, Xuechuan.(2017).Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels.JOURNAL OF MEDICINAL CHEMISTRY,60(11),4680-4692.
MLA	Qu, Chunrong,et al."Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels".JOURNAL OF MEDICINAL CHEMISTRY 60.11(2017):4680-4692.