Substituted N -(biphenyl-4′-yl)methyl (R)-2-acetamido-3- methoxypropionamides: Potent anticonvulsants that affect frequency (Use) dependence and slow inactivation of sodium channels

We prepared 13 derivatives of N-(biphenyl-4′-yl)methyl (R)-2-acetamido-3-methoxypropionamide that differed in type and placement of a R-substituent in the terminal aryl unit. We demonstrated that the R-substituent impacted the compound's whole animal and cellular pharmacological activities. In rodents, select compounds exhibited excellent anticonvulsant activities and protective indices (PI = TD₅₀/ED₅₀) that compared favorably with clinical antiseizure drugs. Compounds with a polar, aprotic R-substituent potently promoted Na⁺ channel slow inactivation and displayed frequency (use) inhibition of Na⁺ currents at low micromolar concentrations. The possible advantage of affecting these two pathways to decrease neurological hyperexcitability is discussed.