Discovery and Optimization of Selective Nav1.8 Modulator Series That Demonstrate Efficacy in Preclinical Models of Pain

Sharan K Bagal; Peter J Bungay; Stephen M Denton; Karl R Gibson; Melanie S Glossop; Tanya L Hay; Mark I Kemp; Charlotte A L Lane; Mark L Lewis; Graham N Maw; William A Million; C Elizabeth Payne; Cedric Poinsard; David J Rawson; Blanda L Stammen; Edward B Stevens; Lisa R Thompson

doi:10.1021/acsmedchemlett.5b00059

Discovery and Optimization of Selective Nav1.8 Modulator Series That Demonstrate Efficacy in Preclinical Models of Pain

ACS Med Chem Lett. 2015 Apr 29;6(6):650-4. doi: 10.1021/acsmedchemlett.5b00059. eCollection 2015 Jun 11.

Authors

Sharan K Bagal¹, Peter J Bungay², Stephen M Denton³, Karl R Gibson³, Melanie S Glossop³, Tanya L Hay³, Mark I Kemp³, Charlotte A L Lane³, Mark L Lewis³, Graham N Maw³, William A Million³, C Elizabeth Payne², Cedric Poinsard³, David J Rawson³, Blanda L Stammen³, Edward B Stevens², Lisa R Thompson³

Affiliations

¹ Worldwide Medicinal Chemistry, Pfizer Neusentis , The Portway Building, Granta Park, Great Abington, Cambridge CB21 6GS, U.K.
² Neusentis U.K., Pfizer Global R&D , The Portway Building, Granta Park, Cambridge CB21 6GS, U.K.
³ Worldwide Medicinal Chemistry, Pfizer Global R&D , Sandwich CT13 9NJ, U.K.

Abstract

Voltage-gated sodium channels, in particular Nav1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we described the optimization of Nav1.8 modulator series to deliver subtype selective, state, and use-dependent chemical matter that is efficacious in preclinical models of neuropathic and inflammatory pain.

Keywords: Nav1.8; SCN10A; TTX-R; Voltage-gated sodium channels; sodium channel drugs.