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
  • 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: [email protected].
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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