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, both gain-of-function and loss-of-function. Consequently, there has been considerable interest in the development of an isoform-selective NaV1.7 inhibitor for the management of chronic neuropathic pain. This presentation will describe our efforts to leverage atropisomerism to balance DDI liabilities, pharmacokinetic parameters, and sodium channel isoform selectivity in the identification of heteroaryl sulfonamide-derived NaV1.7 inhibitors with robust in vivo analgesic activity.

Leveraging atropisomerism in the identification of NaV1.7 inhibitors for the treatment of pain

255th National Meeting (2018)

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