Synthesis and SAR of 1,2-trans-(1-hydroxy-3-phenylprop-1-yl)cyclopentane carboxamide derivatives, a new class of sodium channel blockers

Novel cyclopentane-based 3-phenyl-1-hydroxypropyl compounds were evaluated for inhibitory activity against the peripheral nerve sodium channel NaV1.7 and off-target activity against the cardiac potassium channel hERG. The stereochemistry of the hydroxyl group and substitution on the phenyl rings with either fluorinated O-alkyl or alkyl groups were found to be critical for conferring potency against NaV1.7. A benchmark compound from this series displayed efficacy in rat models of inflammatory and neuropathic pain.

Graphical abstractNovel cyclopentane-based 3-phenyl-1-hydroxypropyl compounds were evaluated for inhibitory activity against the peripheral nerve and sodium channel NaV1.7 and off-target activity against the cardiac potassium channel hERG.Figure optionsDownload full-size imageDownload as PowerPoint slide