Synthesis and Biological Evaluation of Pyrrolidine-based T-type Calcium Channel Inhibitors for the Treatment of Neuropathic Pain

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2018 Sep 21

PMID 30231778

Citations 2

Authors

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

Affiliations

Soon will be listed here.

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 Ca3.1 and Ca3.2 channel inhibitory activities. Among potent inhibitors against both Ca3.1 and Ca3.2 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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