- 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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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.
- Ogiyama, Takashi,Yonezawa, Koichi,Inoue, Makoto,Katayama, Naoko,Watanabe, Toshihiro,Yoshimura, Seiji,Gotoh, Takayasu,Kiso, Tetsuo,Koakutsu, Akiko,Kakimoto, Shuichiro,Shishikura, Jun-Ichi
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p. 4638 - 4648
(2015/08/03)
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- 1-SUBSTITUTED TETRAHYDROISOQUINOLINE COMPOUND
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Provided is a compound useful as an N-type Ca2+ channel blocker. As a result of intensive studies of compounds having an action of blocking N-type Ca2+ channels, the present inventors found that a tetrahydroisoquinoline compound of the present invention having a substituent at the 1-position has an action of blocking the N-type Ca2+ channels, an antinociceptive pain action, an antineuropathic pain action, an abdominal pain-inhibitory action and an opioid-induced constipation-improving action, and the present invention has been completed based on these findings. The compound of the present invention can be used as a pharmaceutical composition for preventing and/or treating various pains such as neuropathic pain and nociceptive pain, headaches such as migraine and cluster headache, central nervous system diseases such as anxiety, depression, epilepsy, cerebral stroke and restless legs syndrome, abdominal symptoms such as abdominal pain and abdominal distension, stool abnormalities such as diarrhea and constipation, digestive system diseases such as irritable bowel syndrome, urinary system diseases such as overactive bladder and interstitial cystitis, etc.
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Page/Page column 39
(2010/03/02)
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