The voltage-gated sodium channel NaV1.7 serves as a primary driver of action potential firing and neuronal excitability in the pain processing pathway. Genetic evidence supports the role of NaV1.7 in a range of inherited pain syndromes. Consequently, there has been considerable interest in the development of a subtype selective NaV1.7 inhibitor for the management of chronic neuropathic pain. Herein, we provide an in depth analysis of the in vitro and in vivo pharmacokinetic and pharmacodynamic parameters for several sub-series of heteroaryl sulfonamide NaV1.7 inhibitors. Lessons learned led to the discovery of sulfonamides with favorable rat, dog, and cyno pharmacokinetic profiles that demonstrate robust efficacy in several mouse pain models, including UVB and capsaicin-induced nociception.

Defining the pharmacokinetic and pharmacodynamic parameters of potent and selective heteroaryl sulfonamide NaV1.7 inhibitors with robust in vivo analgesic activity

254th National Meeting (2017)

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