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

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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
Issue number1
Publication statusPublished - 2018 Jan 1


All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery

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