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

Research output: Contribution to journalArticle

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 v 3.1 and Ca v 3.2 channel inhibitory activities. Among potent inhibitors against both Ca v 3.1 and Ca v 3.2 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 languageEnglish
Pages (from-to)1460-1471
Number of pages12
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume33
Issue number1
DOIs
Publication statusPublished - 2018 Jan 1

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T-Type Calcium Channels
Neuralgia
Therapeutics
Animal Models
pyrrolidine
Pharmacokinetics
Clinical Trials
Brain

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery

Cite this

Yang, Hak Kyun ; Son, Woo Seung ; Lim, Keon Seung ; Kim, Gun Hee ; Lim, Eun Jeong ; Gadhe, Changdev G. ; Lee, Jae Yeol ; Jeong, Kyu-Sung ; Lim, Sang Min ; Pae, Ae Nim. / Synthesis and biological evaluation of pyrrolidine-based T-type calcium channel inhibitors for the treatment of neuropathic pain. In: Journal of Enzyme Inhibition and Medicinal Chemistry. 2018 ; Vol. 33, No. 1. pp. 1460-1471.
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Synthesis and biological evaluation of pyrrolidine-based T-type calcium channel inhibitors for the treatment of neuropathic pain. / Yang, Hak Kyun; Son, Woo Seung; Lim, Keon Seung; Kim, Gun Hee; Lim, Eun Jeong; Gadhe, Changdev G.; Lee, Jae Yeol; Jeong, Kyu-Sung; Lim, Sang Min; Pae, Ae Nim.

In: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol. 33, No. 1, 01.01.2018, p. 1460-1471.

Research output: Contribution to journalArticle

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AU - Lim, Eun Jeong

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