A highly
potent, selective NaV1.7 inhibitor, DS-1971a,
has been discovered. Exploration of the left-hand phenyl ring of sulfonamide
derivatives (I and II) led to the discovery
of novel series of cycloalkane derivatives with high NaV1.7 inhibitory potency in vitro. As the right-hand heteroaromatic
ring affected the mechanism-based inhibition liability of CYP3A4,
replacement of this moiety resulted in the generation of 4-pyrimidyl
derivatives. Additionally, GSH adducts formation, which can cause
idiosyncratic drug toxicity, was successfully avoided by this modification.
An additional optimization led to the discovery of DS-1971a. In preclinical
studies, DS-1971a demonstrated highly potent selective in vitro profile
with robust efficacy in vivo. DS-1971a exhibited a favorable toxicological
profile, which enabled multiple-dose studies of up to 600 mg bid or
400 mg tid (1200 mg/day) administered for 14 days to healthy human
males. DS-1971a is expected to exert potent efficacy in patients with
peripheral neuropathic pain, with a favorable safety profile.