The discovery of a potent Nav1.3 inhibitor with good oral pharmacokinetics† †All authors are, or were at the time of the work being undertaken, employees of Pfizer

An aryl ether series of potent and selective Na v 1.3 inhibitors is described, starting from a series of diphenymethyl amides. In this article, we describe the discovery of an aryl ether series of potent and selective Na v 1.3 inhibitors. Based on structural analogy to a similar series of compounds we have previously shown bind to the domain IV voltage sensor region of Na v channels, we propose this series binds in the same location. We describe the development of this series from a published starting point, highlighting key selectivity and potency data, and several studies designed to validate Na v 1.3 as a target for pain.