Discovery of an 8-methoxytetrahydroisoquinoline derivative as an orally active N-type calcium channel blocker for neuropathic pain without CYP inhibition liability

[Display omitted] 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 CY...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2015-08, Vol.23 (15), p.4638-4648
Main Authors: Ogiyama, Takashi, Yonezawa, Koichi, Inoue, Makoto, Katayama, Naoko, Watanabe, Toshihiro, Yoshimura, Seiji, Gotoh, Takayasu, Kiso, Tetsuo, Koakutsu, Akiko, Kakimoto, Shuichiro, Shishikura, Jun-ichi
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Calcium Channel Blockers - pharmacology
CaV2.2
Cell Line, Tumor
CYP2D6
CYP3A4
Cytochrome P-450 Enzyme Inhibitors - pharmacology
Humans
Isoquinolines - administration & dosage
Isoquinolines - chemical synthesis
Isoquinolines - pharmacology
Isoquinolines - therapeutic use
N-type calcium channel
Neuralgia - drug therapy
Pain
Rats
Rats, Sprague-Dawley
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Summary:[Display omitted] 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 2.8mg/kg.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2015.05.053