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 Shen; Hongbo Wang; Michael X. Zhu; Xuechuan Hong

doi:10.1021/acs.jmedchem.7b00304

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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.

Original language	English (US)
Pages (from-to)	4680-4692
Number of pages	13
Journal	Journal of medicinal chemistry
Volume	60
Issue number	11
DOIs	https://doi.org/10.1021/acs.jmedchem.7b00304
State	Published - Jun 8 2017

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.7b00304

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Qu, C., Ding, M., Zhu, Y., Lu, Y., Du, J., Miller, M., Tian, J., Zhu, J., Xu, J., Wen, M., Er-Bu, A. G. A., Wang, J., Xiao, Y., Wu, M., McManus, O. B., Li, M., Wu, J., Luo, H. R., Cao, Z., ... Hong, X. (2017). Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels. Journal of medicinal chemistry, 60(11), 4680-4692. https://doi.org/10.1021/acs.jmedchem.7b00304

Qu, C, Ding, M, Zhu, Y, Lu, Y, Du, J, Miller, M, Tian, J, Zhu, J, Xu, J, Wen, M, Er-Bu, AGA, Wang, J, Xiao, Y, Wu, M, McManus, OB, Li, M, Wu, J, Luo, HR, Cao, Z, Shen, B, Wang, H, Zhu, MX & Hong, X 2017, 'Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels', Journal of medicinal chemistry, vol. 60, no. 11, pp. 4680-4692. https://doi.org/10.1021/acs.jmedchem.7b00304

@article{58fed8c710fe4e6fb04956df15ea482a,

title = "Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels",

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.",

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

note = "Funding Information: This work was partially supported by grants from NSFC (81573383 21390402), NSFHP (2014CFB704), IS&TCPC (2015DFA30440, 2014cFB30020) the Applied Basic Research Program of Wuhan Municipal Bureau of Science & Technology, the Applied Basic Research Programs of Scientific and Technologic Council of Suzhou (SYG201521), Natural Science Foundation of Jiangsu Province (BK20160387), Beijing Nova Plan Z (131107000413063) the Fundamental Research Funds for the Central Universities and U.S. National Institutes of Health (NS056942, NS092377, U54 MH084691). Publisher Copyright: {\textcopyright} 2017 American Chemical Society.",

year = "2017",

month = jun,

day = "8",

doi = "10.1021/acs.jmedchem.7b00304",

language = "English (US)",

volume = "60",

pages = "4680--4692",

journal = "Journal of medicinal chemistry",

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T1 - Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels

AU - Qu, Chunrong

AU - Ding, Mingmin

AU - Zhu, Yingmin

AU - Lu, Yungang

AU - Du, Juan

AU - Miller, Melissa

AU - Tian, Jinbin

AU - Zhu, Jinmei

AU - Xu, Jian

AU - Wen, Meng

AU - Er-Bu, A. G.A.

AU - Wang, Jule

AU - Xiao, Yuling

AU - Wu, Meng

AU - McManus, Owen B.

AU - Li, Min

AU - Wu, Jilin

AU - Luo, Huai Rong

AU - Cao, Zhengyu

AU - Shen, Bing

AU - Wang, Hongbo

AU - Zhu, Michael X.

AU - Hong, Xuechuan

N1 - Funding Information: This work was partially supported by grants from NSFC (81573383 21390402), NSFHP (2014CFB704), IS&TCPC (2015DFA30440, 2014cFB30020) the Applied Basic Research Program of Wuhan Municipal Bureau of Science & Technology, the Applied Basic Research Programs of Scientific and Technologic Council of Suzhou (SYG201521), Natural Science Foundation of Jiangsu Province (BK20160387), Beijing Nova Plan Z (131107000413063) the Fundamental Research Funds for the Central Universities and U.S. National Institutes of Health (NS056942, NS092377, U54 MH084691). Publisher Copyright: © 2017 American Chemical Society.

PY - 2017/6/8

Y1 - 2017/6/8

N2 - 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.

AB - 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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U2 - 10.1021/acs.jmedchem.7b00304

DO - 10.1021/acs.jmedchem.7b00304

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AN - SCOPUS:85020464352

SN - 0022-2623

VL - 60

SP - 4680

EP - 4692

JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

IS - 11

ER -

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

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