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.
Highlights
Neuropathic pain is chronic pain originated from lesions or diseases of the peripheral or central somatosensory nervous system[1]
All reactions were monitored by analytical thin layer chromatography (TLC) using glass pates pre-coated with silica gel from Merck (0.25 mm, 60 Å pore-size) impregnated with a fluorescent indicator (254 nm)
Our initial molecular structure was constructed via a structure-hybridisation between the template of TTA-P2 or Z-944 and 5-isobutyl-1-phenyl-1H-pyrazole moiety that consistently showed robust activity in our previous T-type inhibitors (Figure 2)[50,51]. This compound series accommodating hydrophobic R group are well mapped with 3D ligand-based pharmacophore that was produced by common feature hypothesis generation approach (HipHop) implemented in CATALYST program for the rational design of T-type calcium channel inhibitors (Figure 3)[52]
Summary
Neuropathic pain is chronic pain originated from lesions or diseases of the peripheral or central somatosensory nervous system[1]. Current therapeutic options for neuropathic pain include anti-convulsants such as sodium and calcium channel blockers, anti-depressants, opioids, NSAIDs, cannabinoids, topical agents, and combinations of these drugs[2,3]. Administration of these drugs only reduce 30–50% of pain in approximately 50% of neuropathic pain patients[4,5]. Identification of potential biomarkers for each type of neuropathic pain and subsequent development of chemical probes that can modulate the biomarkers will provide exciting opportunities to better understand the heterogeneity of neuropathic pain and produce efficacious pain drugs[6,7]
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