TY - JOUR
T1 - Synthesis and anticonvulsant activity of a new class of 2- [(arylalkyl)amino]alkanamide derivatives
AU - Pevarello, Paolo
AU - Bonsignori, Alberto
AU - Dostert, Philippe
AU - Heidempergher, Franco
AU - Pinciroli, Vittorio
AU - Colombo, Maristella
AU - McArthur, Robert A.
AU - Salvati, Patricia
AU - Post, Claes
AU - Fariello, Ruggero G.
AU - Varasi, Mario
PY - 1998/2/12
Y1 - 1998/2/12
N2 - 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.
AB - 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.
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U2 - 10.1021/jm970599m
DO - 10.1021/jm970599m
M3 - Article
C2 - 9484507
AN - SCOPUS:15144352587
VL - 41
SP - 579
EP - 590
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 4
ER -