The voltage-gated sodium (Nav) family of ion channels play a key role in regulation of cellular excitability and Nav inhibitors are used clinically as analgesics and local anesthetics. However, a lack of isoform selectivity with existing blockers results in dose-limiting toxicity due to central nervous system and cardiac side effects. Channel subtype Nav1.7 has been shown to be essential for the normal sensation of pain and has been linked to pain syndromes such as inherited erythromelalgia (IEM) and congenital indifference to pain (CIP). This genetic validation for Nav1.7 as a target for therapy prompted a significant drug discovery program focused on delivery of small molecule inhibitors with enhanced selectivity over existing clinical agents. This presentation will cover the identification and optimisation of an aryl sulphonamide series of Nav1.7 inhibitors. Hit to lead studies and medicinal chemistry challenges of working in acidic drug space will be described including the SAR that led to identification of clinical candidate PF-05089771. Furthermore, the Nav subtype selectivity and interaction site that is distinct from that of the classical non-selective pore blocking drugs will also be discussed.

Discovery of PF-05089771: A potent, subtype selective Nav1.7 inhibitor for the treatment of pain

251st National Meeting (2016)

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