Ogiyama Takashi, Inoue Makoto, Honda Shugo, Yamada Hiroyoshi, Watanabe Toshihiro, Gotoh Takayasu, Kiso Tetsuo, Koakutsu Akiko, Kakimoto Shuichiro, Shishikura Jun-ichi
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Bioorg Med Chem. 2014 Dec 15;22(24):6899-907. doi: 10.1016/j.bmc.2014.10.020. Epub 2014 Oct 22.
N-type calcium channels represent a promising target for the treatment of neuropathic pain. The selective N-type calcium channel blocker ziconotide ameliorates severe chronic pain but has a narrow therapeutic window and requires intrathecal administration. We identified tetrahydroisoquinoline derivative 1a as a novel potent N-type calcium channel blocker. However, this compound also exhibited potent inhibitory activity against hERG channels. Structural optimizations led to identification of (1S)-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-{[(1-hydroxycyclohexyl)methyl]amino}ethanone ((S)-1h), which exhibited high selectivity for hERG channels while retaining potency for N-type calcium channel inhibition. (S)-1h went on to demonstrate in vivo efficacy as an orally available N-type calcium channel blocker in a rat spinal nerve ligation model of neuropathic pain.
N型钙通道是治疗神经性疼痛的一个有前景的靶点。选择性N型钙通道阻滞剂齐考诺肽可改善严重的慢性疼痛，但治疗窗狭窄且需要鞘内给药。我们鉴定出四氢异喹啉衍生物1a是一种新型强效N型钙通道阻滞剂。然而，该化合物对hERG通道也表现出强效抑制活性。通过结构优化，鉴定出(1S)-(1-环己基-3,4-二氢异喹啉-2(1H)-基)-2-{[(1-羟基环己基)甲基]氨基}乙酮((S)-1h)，其对hERG通道具有高选择性，同时保留了对N型钙通道抑制的效力。(S)-1h进而在神经性疼痛大鼠脊髓神经结扎模型中作为一种口服可用的N型钙通道阻滞剂证明了体内疗效。
