A STRUCTURE-ACTIVITY RELATIONSHIP STUDY OF NOVEL PHENYLACETAMIDES WHICH ARE SODIUM-CHANNEL BLOCKERS

A structure-activity relationship study of a series of novel Na+ chann el blockers, structurally related to 1-piperidinyl)propyl]-alpha-pheny lbenzeneacetamide (1, PD85639) is described. The diphenylacetic acid p ortion of the molecule was left unchanged throughout the study, while structural features in the amine portion and the amide alkyl linkage o f the molecule were modified. The compounds were tested for inhibition of veratridine-stimulated Na+ influx in CHO cells expressing type IIA Na+ channels. Several derivatives show a trend toward more potent Na channel blockade activity with increasing lipophilicity of the amine portion of the molecule. The presence of a phenyl ring near the amine increases inhibitory potency. A three-carbon spacer between the amide and amine is optimal, and a secondary amide linkage is preferred.