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

Authors

Christian E Gerber, Bartlomiej S Augustynek, Philipp Grossenbacher, Barbara Hauert, Simon A Singer, Christine Peinelt, Martin Lochner

Published in

Journal of medicinal chemistry. Apr 13, 2026. Epub Apr 13, 2026.

Abstract

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.

PMID:
41968916
Bibliographic data and abstract were imported from PubMed on 13 Apr 2026.

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