title: Synthesis and anticonvulsant activity of a new class of 2-[(arylalky)amino]alkanamide derivatives.
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.
authors.affiliation: Department of Chemistry, CNS Preclinical Research, Nerviano, MI, Italy. paolo.pevarello@eu.pnu.com
authors.forename: P
authors.initials: P
authors.lastname: Pevarello
authors.forename: A
authors.initials: A
authors.lastname: Bonsignori
authors.forename: P
authors.initials: P
authors.lastname: Dostert
authors.forename: F
authors.initials: F
authors.lastname: Heidempergher
authors.forename: V
authors.initials: V
authors.lastname: Pinciroli
authors.forename: M
authors.initials: M
authors.lastname: Colombo
authors.forename: R A
authors.initials: RA
authors.lastname: McArthur
authors.forename: P
authors.initials: P
authors.lastname: Salvati
authors.forename: C
authors.initials: C
authors.lastname: Post
authors.forename: R G
authors.initials: RG
authors.lastname: Fariello
authors.forename: M
authors.initials: M
authors.lastname: Varasi
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001596:Benzylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001640:Bicuculline; D015195:Drug Design; D004597:Electroshock; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D010852:Picrotoxin; D004856:Postural Balance / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D013329:Structure-Activity Relationship; D013331:Strychnine
chemical_list: D000409:Alanine; D000927:Anticonvulsants; D001596:Benzylamines; D001640:Bicuculline; D007202:Indicators and Reagents; D010852:Picrotoxin; D013331:Strychnine; C092797:safinamide