2. Academic Validation
  3. 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

  • Bioorg Med Chem. 2019 Jan 1;27(1):230-239. doi: 10.1016/j.bmc.2018.12.002.
Alan D Brown 1,  Sharan K Bagal 1,  Paul Blackwell 2,  David C Blakemore 3,  Bruce Brown 2,  Peter J Bungay 4,  Martin Corless 2,  James Crawforth 2,  David Fengas 5,  David R Fenwick 2,  Victoria Gray 2,  Mark Kemp 2,  Wolfgang Klute 2,  Laia Malet Sanz 2,  Duncan Miller 2,  Yoshihisa Murata 2,  C Elizabeth Payne 4,  Sarah Skerratt 1,  Edward B Stevens 4,  Joseph S Warmus 6
Affiliations

Affiliations

  • 1 Pfizer Medicine Design, Pfizer Ltd., The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
  • 2 Pfizer Medicinal Sciences, Pfizer Global R&D, Sandwich CT13 9FF, UK.
  • 3 Pfizer Medicine Design, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA.
  • 4 Medicinal Sciences, Pfizer Ltd., The Portway Building, Granta Park, Cambridge CB21 6GS, UK.
  • 5 Concept Life Sciences, Discovery Park, Ramsgate Road, Sandwich, Kent CT13 9FF, UK.
  • 6 Pfizer Medicine Design, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. Electronic address: Joseph.Warmus@pfizer.com.
PMID: 30538065 DOI: 10.1016/j.bmc.2018.12.002
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.

Keywords

Benzimidazole; Inflammatory pain; Na(V)1.8; Neuropathic pain; PF-06305591; SCN10A; Voltage gated sodium channel.

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