The discovery of a potent Nav1.3 inhibitor with good oral pharmacokinetics.

In this article, we describe the discovery of an aryl ether series of potent and selective Nav1.3 inhibitors. Based on structural analogy to a similar series of compounds we have previously shown bind to the domain IV voltage sensor region of Nav 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 Nav1.3 as a target for pain.

Development of dirhodium(II)-catalyzed generation and enantioselective 1,3-dipolar cycloaddition of carbonyl ylides.

Catalytic, enantioselective, tandem carbonyl ylide formation/cycloaddition of 2-diazo-3,6-diketoester 2 with the use of dirhodium tetrakiscarboxylate and tetrakisbinaphtholphosphate catalysts to give the cycloadducts 3 in good yields and up to 90% ee is described.