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6-吡唑甲酰胺基-3N-取代氮杂双环[3,1,0]己烷衍生物作为治疗神经性疼痛的T型钙通道抑制剂的合成与评价

Synthesis and evaluation of 6-pyrazoylamido-3N-substituted azabicyclo[3,1,0]hexane derivatives as T-type calcium channel inhibitors for treatment of neuropathic pain.

作者信息

Kim Jung Hyun, Nam Ghilsoo

机构信息

Center for Neuro-Medicine, Brain Science Institute, Korea Institutes of Science and Technology (KIST), Seoul 136-791, Republic of Korea.

Center for Neuro-Medicine, Brain Science Institute, Korea Institutes of Science and Technology (KIST), Seoul 136-791, Republic of Korea; School of Science, University of Science and Technology, Daejeon 305-333, Republic of Korea.

出版信息

Bioorg Med Chem. 2016 Nov 1;24(21):5028-5035. doi: 10.1016/j.bmc.2016.06.006. Epub 2016 Jun 4.

DOI:10.1016/j.bmc.2016.06.006
PMID:27591007
Abstract

A new series of aryls, including benzo[d]imidazole/isoxazole/pyrazole, conjugated to 3N-substituted-azabicyclo[3.1.0]hexane derivatives were designed and synthesized as inhibitors of T-type calcium channels. Among the synthesized compounds, 3N-R-substituted azabicyclo[3.1.0]hexane carboxamide derivatives containing 5-isobutyl-1-phenyl-pyrazole ring exhibited potent and selective T-channel inhibition and good metabolic stability without CYP450 inhibition. Compounds 10d and 10e contained hydrophobic substituents at the 3N-position and exhibited potent in vitro efficacy, as well as neuropathic pain alleviation in rats.

摘要

设计并合成了一系列新型芳基化合物，包括与3-N-取代氮杂双环[3.1.0]己烷衍生物共轭的苯并[d]咪唑/异恶唑/吡唑，作为T型钙通道抑制剂。在合成的化合物中，含有5-异丁基-1-苯基吡唑环的3-N-R-取代氮杂双环[3.1.0]己烷甲酰胺衍生物表现出强效且选择性的T通道抑制作用以及良好的代谢稳定性，且无CYP450抑制作用。化合物10d和10e在3-N位含有疏水取代基，表现出强效的体外药效以及对大鼠神经性疼痛的缓解作用。

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