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A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective Na1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective Na1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.

For many patients the current therapies for controlling chronic pain are inadequate. This has driven the search for analgesics with improved efficacy and side effect profiles. Some anticonvulsants have voltage-gated Na(+) channels (VGSCs) as their molecular targets and are used to treat pain, but the efficacy seen is marginal and the drugs are generally poorly tolerated. The clinically used VGSC-modulating analgesics show no isoform selectivity, which probably limits their use. Thus, focus has fallen on VGSCs expressed selectively by primary afferent neurons and the search for isoform-selective drugs. In this review, we describe developments in our understanding of the biology of VGSCs, screening technologies and the pharmacological properties of VGSC modulators with promise as analgesics. Also highlighted are the challenges associated with targeting isoform-selective VGSCs.

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