The discovery and optimization of benzimidazoles as selective NaV1.8 blockers for the treatment of pain

Article abstract of DOI:10.1016/j.bmc.2018.12.002

The voltage gated sodium channel Na_V1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole Na_V1.8 blockers. Subsequent optimization allowed the identification of compound 9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile.