The discovery and optimization of benzimidazoles as selective NaV1.8 blockers for the treatment of pain. Issue 1 (1st January 2019)

• Record Type: Journal Article
• Authors: Brown, Alan D.; Bagal, Sharan K.; Blackwell, Paul; Blakemore, David C.; Brown, Bruce; Bungay, Peter J.; Corless, Martin; Crawforth, James; Fengas, David; Fenwick, David R.; Gray, Victoria; Kemp, Mark; Klute, Wolfgang; Malet Sanz, Laia; Miller, Duncan; Murata, Yoshihisa; Payne, C. Elizabeth; Skerratt, Sarah; Stevens, Edward B.; Warmus, Joseph S.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 1(2019)
• Page Start: 230
• Page End: 239
• Publication Date: 2019-01-01
• Subjects: Benzimidazole -- PF-06305591 -- Neuropathic pain -- Inflammatory pain -- Voltage gated sodium channel -- NaV1.8 -- SCN10A; ADMET absorption, distribution, metabolism, excretion and toxicity -- AUC area under the concentration versus time curve -- Clp plasma clearance -- Clu unbound clearance -- F bioavailability -- HLM human liver microsomes -- hERG human ether–a–go–go -- hHeps human hepatocytes -- IC50 half-maximum inhibitory concentration -- PK pharmacokinetics -- PMC parallel medicinal chemistry -- RRCK Ralph Russ canine kidney cell line -- T1/2 half-life -- TPSA topological surface area -- Vd volume of distribution; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.12.002
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The voltage gated sodium channel NaV 1.8 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 NaV 1.8 blockers. Subsequent optimization allowed the identification of compound9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile.