Based on the recently discovered genetic linkage between mutations in gene coding for the NaV1.7 channel protein and inheritable pain states, selectively inhibiting this sodium channel subtype represents an attractive approach to provide analgesia in conditions associated with neuropathic pain. These genetic mutations in NaV1.7 have been identified in both inheritable painful states such as erythromelalgia, as well as congenital insensitivity to pain. NaV1.7 is expressed in the peripheral nervous system and is responsible for the conduction of painful stimuli from nerve endings and along the peripheral afferent fibers to the spinal cord and then to supraspinal sites. NaV1.7 expression is increased in painful neuromas in man, and is increased in pre-clinical models of peripheral neuropathy.One of the main challenges to develop NaV1.7 inhibitors devoid of side effects has been to achieve sufficient selectivity vs. off-targets such as hERG or the other NaV channel subtypes 1.5 and 1.2, which are associated with cardiac and CNS side effects. This contribution will describe AstraZeneca's internal lead generation and lead optimization campaign to identify selective 1.7 inhibitors and the discovery and pharmacological characterization of lead AZD3161.

Discovery and pharmacological characterization of the selective NaV1.7 inhibitor AZD3161

247th National Meeting (2014)

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