Potent Anthranilic Anilide-Based TRPM4 Channel Inhibitors Identified by a Structure–Activity Relationship Study

We report the discovery of novel anthranilic anilide-based compound PBA (118), an inhibitor of Ca2+-activated monovalent cation channel TRPM4. PBA exhibits increased potency, ligand efficiency, aqueous solubility, and lipophilic ligand efficiency, as well as lower cytotoxicity compared to reference inhibitor NBA. The phenyl ring of the 4-chloro-2-(2-phenoxyacetamido)benzoic acid scaffold was found to be essential for activity, and PBA resulted from a focused SAR study conducted on this ring. The meta-position proved to be favorable for substitutions, where lipophilic groups generally led to more potent inhibitors compared to polar substituents. X-ray structures and NMR studies of anthranilic anilides revealed bifurcated intramolecular hydrogen bonds stabilizing a “bent” conformation that might be important for their mode of action. The discovery of TRPM4 inhibitor PBA, together with other findings from our SAR study, will benefit future TRPM4 drug development efforts and research.