Synthesis and biological evaluation of pyrrolidine-based T-type calcium channel inhibitors for the treatment of neuropathic pain

Hak Kyun Yang; Woo Seung Son; Keon Seung Lim; Gun Hee Kim; Eun Jeong Lim; Changdev G. Gadhe; Jae Yeol Lee; Kyu Sung Jeong; Sang Min Lim; Ae Nim Pae

doi:10.1080/14756366.2018.1513926

Synthesis and biological evaluation of pyrrolidine-based T-type calcium channel inhibitors for the treatment of neuropathic pain

Hak Kyun Yang, Woo Seung Son, Keon Seung Lim, Gun Hee Kim, Eun Jeong Lim, Changdev G. Gadhe, Jae Yeol Lee, Kyu Sung Jeong, Sang Min Lim, Ae Nim Pae

Department of Chemistry

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

1 Citation (Scopus)

Abstract

The treatment of neuropathic pain is one of the urgent unmet medical needs and T-type calcium channels are promising therapeutic targets for neuropathic pain. Several potent T-type channel inhibitors showed promising in vivo efficacy in neuropathic pain animal models and are being investigated in clinical trials. Herein we report development of novel pyrrolidine-based T-type calcium channel inhibitors by pharmacophore mapping and structural hybridisation followed by evaluation of their Ca_v3.1 and Ca_v3.2 channel inhibitory activities. Among potent inhibitors against both Ca_v3.1 and Ca_v3.2 channels, a promising compound 20n based on in vitro ADME properties displayed satisfactory plasma and brain exposure in rats according to in vivo pharmacokinetic studies. We further demonstrated that 20n effectively improved the symptoms of neuropathic pain in both SNL and STZ neuropathic pain animal models, suggesting modulation of T-type calcium channels can be a promising therapeutic strategy for the treatment of neuropathic pain.

Original language	English
Pages (from-to)	1460-1471
Number of pages	12
Journal	Journal of Enzyme Inhibition and Medicinal Chemistry
Volume	33
Issue number	1
DOIs	https://doi.org/10.1080/14756366.2018.1513926
Publication status	Published - 2018 Jan 1

Bibliographical note

Funding Information:
This work was supported by the Korea government (MSIP) under the National Research Council of Science & Technology (NST) [grant No. CRC-15-04-KIST].

Publisher Copyright:
© 2018, © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

All Science Journal Classification (ASJC) codes

Pharmacology
Drug Discovery

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10.1080/14756366.2018.1513926

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Yang, H. K., Son, W. S., Lim, K. S., Kim, G. H., Lim, E. J., Gadhe, C. G., Lee, J. Y., Jeong, K. S., Lim, S. M., & Pae, A. N. (2018). Synthesis and biological evaluation of pyrrolidine-based T-type calcium channel inhibitors for the treatment of neuropathic pain. Journal of Enzyme Inhibition and Medicinal Chemistry, 33(1), 1460-1471. https://doi.org/10.1080/14756366.2018.1513926

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abstract = "The treatment of neuropathic pain is one of the urgent unmet medical needs and T-type calcium channels are promising therapeutic targets for neuropathic pain. Several potent T-type channel inhibitors showed promising in vivo efficacy in neuropathic pain animal models and are being investigated in clinical trials. Herein we report development of novel pyrrolidine-based T-type calcium channel inhibitors by pharmacophore mapping and structural hybridisation followed by evaluation of their Cav3.1 and Cav3.2 channel inhibitory activities. Among potent inhibitors against both Cav3.1 and Cav3.2 channels, a promising compound 20n based on in vitro ADME properties displayed satisfactory plasma and brain exposure in rats according to in vivo pharmacokinetic studies. We further demonstrated that 20n effectively improved the symptoms of neuropathic pain in both SNL and STZ neuropathic pain animal models, suggesting modulation of T-type calcium channels can be a promising therapeutic strategy for the treatment of neuropathic pain.",

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AU - Pae, Ae Nim

N1 - Funding Information: This work was supported by the Korea government (MSIP) under the National Research Council of Science & Technology (NST) [grant No. CRC-15-04-KIST]. Publisher Copyright: © 2018, © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

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N2 - The treatment of neuropathic pain is one of the urgent unmet medical needs and T-type calcium channels are promising therapeutic targets for neuropathic pain. Several potent T-type channel inhibitors showed promising in vivo efficacy in neuropathic pain animal models and are being investigated in clinical trials. Herein we report development of novel pyrrolidine-based T-type calcium channel inhibitors by pharmacophore mapping and structural hybridisation followed by evaluation of their Cav3.1 and Cav3.2 channel inhibitory activities. Among potent inhibitors against both Cav3.1 and Cav3.2 channels, a promising compound 20n based on in vitro ADME properties displayed satisfactory plasma and brain exposure in rats according to in vivo pharmacokinetic studies. We further demonstrated that 20n effectively improved the symptoms of neuropathic pain in both SNL and STZ neuropathic pain animal models, suggesting modulation of T-type calcium channels can be a promising therapeutic strategy for the treatment of neuropathic pain.

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Synthesis and biological evaluation of pyrrolidine-based T-type calcium channel inhibitors for the treatment of neuropathic pain

Abstract

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