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

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

Sharan K Bagal  1 , Peter J Bungay  2 , Stephen M Denton  3 , Karl R Gibson  3 , Melanie S Glossop  3 , Tanya L Hay  3 , Mark I Kemp  3 , Charlotte A L Lane  3 , Mark L Lewis  3 , Graham N Maw  3 , William A Million  3 , C Elizabeth Payne  2 , Cedric Poinsard  3 , David J Rawson  3 , Blanda L Stammen  3 , Edward B Stevens  2 , Lisa R Thompson  3
Affiliations

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

Sharan K Bagal et al. ACS Med Chem Lett. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Discovery of candidate compound 3. IC50 data generated in VSP-FRET at hNav1.8 in HEK293 cells (in house cell line) with at least three tests on three different assay runs. TTX-S data generated in VSP-FRET in SHSY5Y neuroblastoma cell line expressing hNav1.2, hNav1.3, and hNav1.7.
Figure 2
Figure 2
Antiallodynic effects of 13 in the TNT model of neuropathic pain. Error bars represent the SEM. A single dose of 40 mg/kg of 13 equivalent to a free plasma exposure of 0.2 μM, significantly shifted the 50% paw withdrawal threshold in the ipsilateral paw from a baseline of 1.7 ± 0.3 to 7.3 ± 1.8 g, 1.5 h after dosing (*P < 0.05). These effects were comparable to 10 mg/kg of Pregabalin, which shifted the 50% paw withdrawal threshold in the ipsilateral hindpaw from 1.7 ± 0.2 to 5.8 ± 1.7 g, 1.5 h after dosing (P = 0.07).
Scheme 1
Scheme 1. Preparation of Compound 3
Scheme 2
Scheme 2. Preparation of Compound 13
See this image and copyright information in PMC

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