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

Abstract

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.

• Authors: Takashi Ogiyama, Koichi Yonezawa, Makoto Inoue, Naoko Katayama, Toshihiro Watanabe, Seiji Yoshimura, Takayasu Gotoh, Tetsuo Kiso, Akiko Koakutsu, Shuichiro Kakimoto, Jun-Ichi Shishikura
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 23 Issue 15 Pg. 4638-4648 (Aug 01 2015) ISSN: 1464-3391 [Electronic] England
• PMID: 26078010 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Calcium Channel Blockers
• Cytochrome P-450 Enzyme Inhibitors
• Isoquinolines

Topics

• Administration, Oral
• Animals
• Calcium Channel Blockers (pharmacology)
• Cell Line, Tumor
• Cytochrome P-450 Enzyme Inhibitors (pharmacology)
• Humans
• Isoquinolines (administration & dosage, chemical synthesis, pharmacology, therapeutic use)
• Neuralgia (drug therapy)
• Rats
• Rats, Sprague-Dawley