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-{[(2 R )-2-hydroxypropyl]amino}-1-[(1 S )-8-methoxy-1-phenyl-3,4-dihydroisoquinolin-2(1 H )-yl]ethanone ((1 S )- 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 (1 S )- 8t , which eliminated CYP2D6 inhibition liability. Oral administration of (1 S )- 8t exerted efficacy in a rat spinal nerve ligation (SNL) model of neuropathic pain with an ED 50 value of 2.8 mg/kg.