2. Academic Validation
  3. Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels

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

  • J Med Chem. 2017 Jun 8;60(11):4680-4692. doi: 10.1021/acs.jmedchem.7b00304.
Chunrong Qu 1,  Mingmin Ding 1,  Yingmin Zhu 2,  Yungang Lu 2,  Juan Du 3,  Melissa Miller 4,  Jinbin Tian 2,  Jinmei Zhu 1,  Jian Xu 5 6,  Meng Wen 1,  Aga Er-Bu 7,  Jule Wang 7,  Yuling Xiao 1,  Meng Wu 4,  Owen B McManus 4,  Min Li 4,  Jilin Wu 6 8,  Huai-Rong Luo 9,  Zhengyu Cao 5,  Bing Shen 3,  Hongbo Wang 10,  Michael X Zhu 2 6,  Xuechuan Hong 1 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences , Wuhan, Hubei Province 430071, China.
  • 2 Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston , Houston, Texas 77030, United States.
  • 3 School of Basic Medical Sciences, Anhui Medical University , Hefei, Anhui Province 230032, China.
  • 4 Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
  • 5 State Key Laboratory of Natural Medicines, Jiangsu Provincial Key laboratory for TCM Evaluation and Translational Development, China Pharmaceutical University , Nanjing, Jiangsu Province 211198, China.
  • 6 The International Scientist Working Station of Neuropharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai, 201203, China.
  • 7 Medical College, Tibet University , Lasa, Tibet 850000, China.
  • 8 University of Chinese Academy of Sciences , Beijing, 100049, China.
  • 9 Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences , Kunming, Yunnan Province 650201, China.
  • 10 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University , Yantai, Shangdong Province 264005, China.
PMID: 28395140 DOI: 10.1021/acs.jmedchem.7b00304
Abstract

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.

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