Discovery of an 8-methoxytetrahydroisoquinoline derivative as an orally active N-type calcium channel blocker for neuropathic pain without CYP inhibition liability
Discovery of an 8-methoxytetrahydroisoquinoline derivative as an orally active N-type calcium channel blocker for neuropathic pain without CYP inhibition liability
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DOI：
10.1016/j.bmc.2015.05.053
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发表时间：
2015-08-01
影响因子：
3.5
通讯作者：
Shishikura, Jun-ichi
中科院分区：
文献类型：
--
作者：
Ogiyama, Takashi;Yonezawa, Koichi;Shishikura, Jun-ichi
在从四氢异喹啉(S)-1开始的先导优化工作中，我们确定2-{[(2R)-2-hydroxypropyl]amino}-1-[(1S)-8-methoxy-1-phenyl-3，4-dihydroisoquinolin-2(1H)-yl]ethanone((1S)-8t)是一种新型的口服活性小分子N型钙通道阻滞剂，没有细胞色素P抑制作用。通过降低化合物(S)-1的亲脂性，改善了细胞色素P450 3A4的抑制谱。此外，在四氢异喹啉的C-8位引入甲氧基导致了(1S)-8T的鉴定，从而消除了对CYP2D6的抑制作用。在大鼠脊髓神经结扎(SNL)神经病理性疼痛模型上，口服(1s)-8T的ED50值为2.8 mg/kg。(C)2015爱思唯尔有限公司。保留所有权利。
In lead optimization efforts starting from the tetrahydroisoquinoline (S)-1, we identified 2-{[(2R)-2-hydroxypropyl]amino}-1-[(1S)-8-methoxy-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone((1S)-8t) as a novel orally active small-molecule N-type calcium channel blocker without CYP inhibition liability. CYP3A4 inhibition profile was improved by reducing the lipophilicity of compound (S)-1. Moreover, introduction of a methoxy group to the C-8 position of tetrahydroisoquinoline led to identification of (1S)-8t, which eliminated CYP2D6 inhibition liability. Oral administration of (1S)-8t exerted efficacy in a rat spinal nerve ligation (SNL) model of neuropathic pain with an ED50 value of 2.8 mg/kg. (C) 2015 Elsevier Ltd. All rights reserved.