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.