Synthesis and anticonvulsant activity of a new class of 2- [(arylalkyl)amino]alkanamide derivatives

Paolo Pevarello, Alberto Bonsignori, Philippe Dostert, Franco Heidempergher, Vittorio Pinciroli, Maristella Colombo, Robert A. McArthur, Patricia Salvati, Claes Post, Ruggero G. Fariello, Mario Varasi

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Abstract

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.

Original languageEnglish
Pages (from-to)579-590
Number of pages12
JournalJournal of Medicinal Chemistry
Volume41
Issue number4
DOIs
Publication statusPublished - Feb 12 1998

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ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Pevarello, P., Bonsignori, A., Dostert, P., Heidempergher, F., Pinciroli, V., Colombo, M., McArthur, R. A., Salvati, P., Post, C., Fariello, R. G., & Varasi, M. (1998). Synthesis and anticonvulsant activity of a new class of 2- [(arylalkyl)amino]alkanamide derivatives. Journal of Medicinal Chemistry, 41(4), 579-590. https://doi.org/10.1021/jm970599m