Synthesis and biological evaluation of pyrrolidine-based T-type calcium channel inhibitors for the treatment of neuropathic pain |
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| Authors: | Hak Kyun Yang Woo Seung Son Keon Seung Lim Gun Hee Kim Eun Jeong Lim Changdev G Gadhe |
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| Institution: | 1. Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, Republic of Korea;2. Department of Chemistry, Yonsei University, Seoul, Republic of Korea;3. 1ST Biotherapeutics Inc., Seongnam, Gyeonggi-do, Republic of Korea;4. Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, Republic of Korea |
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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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| Keywords: | Neuropathic pain T-type calcium channel pyrrolidine spinal nerve ligation streptozotocin |
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