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The discovery and optimization of benzimidazoles as selective Na_V1.8 blockers for the treatment of pain

Lookup NU author(s): Duncan MillerORCiD

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Abstract

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.

Publication metadata

Author(s): Brown AD, Bagal SK, Blackwell P, Blakemore DC, Brown B, Bungay PJ, Corless M, Crawforth J, Fengas D, Fenwick DR, Gray V, Kenp M, Klute W, Malet-Sainz L, Miller D, Murata YC, Payne E, Skerratt S, Warmus JS

Publication type: Article

Publication status: Published

Journal: Bioorganic & Medicinal Chemistry

Year: 2019

Volume: 27

Issue: 1

Pages: 230-239

Print publication date: 01/01/2019

Online publication date: 04/12/2018

Acceptance date: 01/12/2018

ISSN (print): 0968-0896

ISSN (electronic): 1464-3391

Publisher: Elsevier

URL: https://doi.org/10.1016/j.bmc.2018.12.002

DOI: 10.1016/j.bmc.2018.12.002

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