Referenced in: none

Automatically associated channels: Kv11.1

Title: Discovery of novel tetrahydroisoquinoline derivatives as orally active N-type calcium channel blockers with high selectivity for hERG potassium channels.

Authors: Takashi Ogiyama, Makoto Inoue, Shugo Honda, Hiroyoshi Yamada, Toshihiro Watanabe, Takayasu Gotoh, Tetsuo Kiso, Akiko Koakutsu, Shuichiro Kakimoto, Jun-Ichi Shishikura

Journal, date & volume: Bioorg. Med. Chem., 2014 Dec 15 , 22, 6899-907

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25456079

Abstract
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.