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

Chunrong Qu, Mingmin Ding, Yingmin Zhu, Yungang Lu, Juan Du, Melissa Miller, Jinbin Tian, Jinmei Zhu, Jian Xu, Meng Wen, A. G.A. Er-Bu, Jule Wang, Yuling Xiao, Meng Wu, Owen B. McManus, Min Li, Jilin Wu, Huai Rong Luo, Zhengyu Cao, Bing ShenHongbo Wang, Michael X. Zhu, Xuechuan Hong

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20 Scopus citations


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 glomerulosclerosis and cancer.

Original languageEnglish (US)
Pages (from-to)4680-4692
Number of pages13
JournalJournal of medicinal chemistry
Issue number11
StatePublished - Jun 8 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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