- The discovery and optimization of benzimidazoles as selective NaV1.8 blockers for the treatment of pain.
The discovery and optimization of benzimidazoles as selective NaV1.8 blockers for the treatment of pain.
Bioorganic & medicinal chemistry (2018-12-13)
Alan D Brown, Sharan K Bagal, Paul Blackwell, David C Blakemore, Bruce Brown, Peter J Bungay, Martin Corless, James Crawforth, David Fengas, David R Fenwick, Victoria Gray, Mark Kemp, Wolfgang Klute, Laia Malet Sanz, Duncan Miller, Yoshihisa Murata, C Elizabeth Payne, Sarah Skerratt, Edward B Stevens, Joseph S Warmus
PMID30538065
ABSTRACT
The voltage gated sodium channel NaV1.8 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 NaV1.8 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.
MATERIALS