The discovery and optimization of benzimidazoles as selective NaV1.8 blockers for the treatment of pain

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

doi:10.1016/j.bmc.2018.12.002

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

Bioorg Med Chem. 2019 Jan 1;27(1):230-239. doi: 10.1016/j.bmc.2018.12.002. Epub 2018 Dec 4.

Authors

Alan D Brown¹, Sharan K Bagal¹, Paul Blackwell², David C Blakemore³, Bruce Brown², Peter J Bungay⁴, Martin Corless², James Crawforth², David Fengas⁵, David R Fenwick², Victoria Gray², Mark Kemp², Wolfgang Klute², Laia Malet Sanz², Duncan Miller², Yoshihisa Murata², C Elizabeth Payne⁴, Sarah Skerratt¹, Edward B Stevens⁴, Joseph S Warmus⁶

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 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.

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

MeSH terms

Benzimidazoles / chemical synthesis
Benzimidazoles / chemistry
Benzimidazoles / pharmacokinetics
Benzimidazoles / pharmacology*
Drug Design
HEK293 Cells
Humans
Molecular Structure
NAV1.8 Voltage-Gated Sodium Channel / metabolism*
Solubility
Structure-Activity Relationship
Voltage-Gated Sodium Channel Blockers / chemical synthesis
Voltage-Gated Sodium Channel Blockers / chemistry
Voltage-Gated Sodium Channel Blockers / pharmacokinetics
Voltage-Gated Sodium Channel Blockers / pharmacology*

Substances

Benzimidazoles
NAV1.8 Voltage-Gated Sodium Channel
Voltage-Gated Sodium Channel Blockers