Efficient Regioselective Synthesis of Benzimidazoles and Azabenzimidazoles to Enable the Rapid Development of Structure–Activity Relationships for Activation of SLACK Potassium Channels

The sodium activated potassium channel known as SLACK (K_Na1.1 or Slo2.2) is widely expressed in the central nervous system and represents a potential target for the treatment of several neurological disorders. While much recent progress has been made toward the discovery of small molecule inhibitors of these channels, reports regarding small molecule activators have been scant. Having identified such compounds via a high-throughput screen, we were interested in establishing structure-activity relationships that could serve as the foundation for the design of potent activators of SLACK channels. In this Letter, we describe the implementation of an efficient synthetic approach to the regioselective synthesis of a series of benzimidazole and azabenzimidazoles based on one of our hit compounds. The key step utilizes a one-pot reduction/formylation/condensation reaction of 2-nitro-arylamines. Also presented herein is functional activity for 15 new analogs prepared by this approach and obtained via a thallium-flux assay in cells stably expressing human wild-type SLACK channels. Many of these new analogs demonstrated substantially improved potency relative to the initial hit compound and provide valuable new data that can be utilized in the design of additional derivatives.