Merging the Structural Motifs of Functionalized Amino Acids and α-Aminoamides: Compounds with Significant Anticonvulsant Activities

Functional amino acids (FAAs) and α-aminoamides (AAAs) are two classes of antiepileptic drugs (AEDs) that exhibit pronounced anticonvulsant activities. We combined key structural pharmacophores present in FAAs and AAAs to generate a new series of compounds and document that select compounds exhibit activity superior to either the prototypical FAA (lacosamide) or the prototypical AAA (safinamide) in the maximal electroshock (MES) seizure model in rats. A representative compound, (R)-N-4′-((3″-fluoro)benzyloxy)benzyl 2-acetamido-3-methoxypropionamide ((R)-10), was tested in the MES (mice, ip), MES (rat, po), psychomotor 6 Hz (32 mA) (mice, ip), and hippocampal kindled (rat, ip) seizure tests providing excellent protection with ED50 values of 13, 14, ~10 mg/kg, and 12 mg/kg, respectively. In the rat sciatic nerve ligation model (ip), (R)-10 (12 mg/kg) provided an 11.2-fold attenuation of mechanical allodynia. In the mouse biphasic formalin pain model (ip), (R)-10 (15 mg/kg) reduced pain responses in the acute and the chronic inflammatory phases

Synthesis and Anticonvulsant Activities of ( R )- N -(4′-Substituted)benzyl 2-Acetamido-3-methoxypropionamides

The structure-activity relationship (SAR) for the N-benzyl group in the clinical antiepileptic agent (R)-lacosamide ((R)-N-benzyl 2-acetamido-3-methoxypropionamide, (R)-3) has been explored. Forty-three compounds were prepared and then evaluated at the National Institute of Neurological Disorders and Stroke Anticonvulsant Screening Program for seizure protection in the maximal electroshock (MES) and subcutaneous Metrazol models. Comparing activities for two series of substituted aryl regioisomers (2′, 3′, 4′) showed that 4′-modified derivatives had the highest activity. Significantly, structural latitude existed at the 4′-site. The SAR indicated that non-bulky 4′-substituted (R)-3 derivatives exhibited superb activity, independent of their electronic properties. Activities in the MES test of several compounds were either comparable with or exceeded that of (R)-3, and surpassed the activities observed for the traditional antiepileptic agents phenytoin, phenobarbital, and valproate