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

• Published in: Bioorganic & medicinal chemistry Vol. 23; no. 15; pp. 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: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.08.2015; Elsevier
• Subjects: Administration, Oral; Animals; Biochemistry & Molecular Biology; Calcium Channel Blockers - pharmacology; CaV2.2; Cell Line, Tumor; Chemistry; Chemistry, Medicinal; Chemistry, Organic; CYP2D6; CYP3A4; Cytochrome P-450 Enzyme Inhibitors - pharmacology; Humans; Isoquinolines - administration & dosage; Isoquinolines - chemical synthesis; Isoquinolines - pharmacology; Isoquinolines - therapeutic use; Life Sciences & Biomedicine; N-type calcium channel; Neuralgia - drug therapy; Pain; Pharmacology & Pharmacy; Physical Sciences; Rats; Rats, Sprague-Dawley; Science & Technology; N-type calcium channel; Pain; CYP3A4; CYP2D6; CaV2.2; SAR; DRUG DISCOVERY
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.05.053

[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.