Discovery and optimisation of potent and highly subtype selective Nav1.8 inhibitors with reduced cardiovascular liabilities

Sharan K. Bagal; Mark I. Kemp; Peter J. Bungay; Tanya L. Hay; Yoshihisa Murata; C. Elizabeth Payne; Edward B. Stevens; Alan Brown; David C. Blakemore; Matthew S. Corbett; Duncan C. Miller; Kiyoyuki Omoto; Joseph S. Warmus

doi:10.1039/C6MD00281A

Discovery and optimisation of potent and highly subtype selective Na_v1.8 inhibitors with reduced cardiovascular liabilities†‡

Sharan K. Bagal,*^a Mark I. Kemp,^b Peter J. Bungay,^c Tanya L. Hay,^d Yoshihisa Murata,^b C. Elizabeth Payne,^e Edward B. Stevens,^e Alan Brown,^a David C. Blakemore,^a Matthew S. Corbett,^f Duncan C. Miller,^b Kiyoyuki Omoto^a and Joseph S. Warmus^f

Author affiliations

* Corresponding authors

^a Worldwide Medicinal Chemistry, Pfizer Global R&D, The Portway Building, Granta Park, Great Abington, Cambridge, UK
E-mail: sharan.bagal@outlook.com

^b Worldwide Medicinal Chemistry, Pfizer Global R&D, Sandwich, UK

^c Pharmacokinetics, Dynamics & Metabolism, Pfizer Global R&D, The Portway Building, Granta Park, Great Abington, Cambridge, UK

^d Pharmacokinetics, Dynamics & Metabolism, Pfizer Global R&D, Sandwich, UK

^e Pfizer Global R&D UK, The Portway Building, Granta Park, Cambridge CB21 6GS, UK

^f Groton Laboratories, Pfizer Global R&D, Eastern Point Road, Groton, Connecticut 06340, USA

Abstract

Voltage-gated sodium channels, in particular Na_v1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we describe the discovery and optimisation of a Na_v1.8 inhibiting phenyl imidazole series that delivers chemical equity that possesses high potency and selectivity and is capable of demonstrating good oral pharmacokinetics.

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Discovery and optimisation of potent and highly subtype selective Na_v1.8 inhibitors with reduced cardiovascular liabilities†‡

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Discovery and optimisation of potent and highly subtype selective Na_v1.8 inhibitors with reduced cardiovascular liabilities

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MedChemComm

Discovery and optimisation of potent and highly subtype selective Nav1.8 inhibitors with reduced cardiovascular liabilities†‡

Abstract

Supplementary files

Article information

Download Citation

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Discovery and optimisation of potent and highly subtype selective Nav1.8 inhibitors with reduced cardiovascular liabilities

Search articles by author

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Discovery and optimisation of potent and highly subtype selective Na_v1.8 inhibitors with reduced cardiovascular liabilities†‡

Discovery and optimisation of potent and highly subtype selective Na_v1.8 inhibitors with reduced cardiovascular liabilities