Yang, Hak Kyun Son, Woo Seung Lim, Keon Seung Kim, Gun Hee Lim, Eun Jeong Gadhe, Changdev G. Lee, Jae Yeol Jeong, Kyu-Sung Lim, Sang Min Pae, Ae Nim 2024-01-19T22:00:15Z 2024-01-19T22:00:15Z 2021-09-03 2018-09-20 1475-6366 https://pubs.kist.re.kr/handle/201004/120904 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. English TAYLOR & FRANCIS LTD RAT SENSORY NEURONS IN-VIVO MIBEFRADIL BLOCK CA2+ CHANNELS MODEL GENE OPTIMIZATION PHARMACOLOGY HYPERALGESIA SULFONAMIDES Synthesis and biological evaluation of pyrrolidine-based T-type calcium channel inhibitors for the treatment of neuropathic pain Article 10.1080/14756366.2018.1513926 1 JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, v.33, no.1, pp.1460 - 1471 JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY 33 1 1460 1471 scie scopus 000452151000001 2-s2.0-85053625658 Biochemistry & Molecular Biology Chemistry, Medicinal Biochemistry & Molecular Biology Pharmacology & Pharmacy Article RAT SENSORY NEURONS IN-VIVO MIBEFRADIL BLOCK CA2+ CHANNELS MODEL GENE OPTIMIZATION PHARMACOLOGY HYPERALGESIA SULFONAMIDES Neuropathic pain T-type calcium channel pyrrolidine spinal nerve ligation streptozotocin