strychnine and safinamide

Although most epilepsies are adequately treated by conventional antiepileptic therapy, there remains an unfulfilled need for safer and more effective anticonvulsant agents. Starting from milacemide, a weak anticonvulsant, and trying to elucidate its mechanism of action, we discovered a structurally novel class of potent and preclinically safe anticonvulsants. Here we report the structure-activity relationship (SAR) study within this series of compounds. Different parts of the structural lead 2-[[4-(3-chlorobenzoxy)benzyl]amino]acetamide (6) were thus varied (Figure 1), and many potent anticonvulsants were found. As an outcome of this study, 57 ((S)-2-[[4-(3-fluorobenzoxy)benzyl]amino]propanamide methanesulfonate, PNU-151774E) emerged as a promising candidate for further development for its potent anticonvulsant activity and outstanding therapeutic indexes (TIs) in different animal tests.

Topics: Alanine; Animals; Anticonvulsants; Benzylamines; Bicuculline; Drug Design; Electroshock; Indicators and Reagents; Male; Mice; Mice, Inbred ICR; Models, Molecular; Molecular Structure; Motor Activity; Picrotoxin; Postural Balance; Rats; Rats, Inbred Strains; Seizures; Structure-Activity Relationship; Strychnine