N-type calcium channels represent a promising target for the treatment of 
neuropathic pain. The selective N-type calcium channel blocker ziconotide 
ameliorates severe chronic pain but has a narrow therapeutic window and requires 
intrathecal administration. We identified tetrahydroisoquinoline derivative 1a 
as a novel potent N-type calcium channel blocker. However, this compound also 
exhibited potent inhibitory activity against hERG channels. Structural 
optimizations led to identification of 
(1S)-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-{[(1-hydroxycyclohexyl)methyl]amino}ethanone 
((S)-1h), which exhibited high selectivity for hERG channels while retaining 
potency for N-type calcium channel inhibition. (S)-1h went on to demonstrate in 
vivo efficacy as an orally available N-type calcium channel blocker in a rat 
spinal nerve ligation model of neuropathic pain.