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.
|Number of pages||12|
|Journal||Journal of Enzyme Inhibition and Medicinal Chemistry|
|Publication status||Published - 2018 Jan 1|
Bibliographical noteFunding 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].
© 2018, © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
All Science Journal Classification (ASJC) codes
- Drug Discovery