title: Synthesis of new perhydropyrrolo[1,2-a]pyrazine derivatives and their evaluation in animal models of epilepsy.
abstract: A series of novel stereochemically pure derivatives of the investigative broad-spectrum anticonvulsant ADD408003 was designed and synthesized. Five-center four-component (U-5C-4CR) and four-center three-component (U-4C-3CR) variants of Ugi reaction were used in the key step of the synthetic pathways. The compounds obtained were evaluated for the anticonvulsant activitiy in the maximal electroshock seizure (MES), subcutaneous Metrazole (scMET) and minimal clonic seizure (6 Hz) animal models of epilepsy. The efficacies of most derivatives in the 6 Hz model of pharmacoresistant partial seizures were markedly higher than in the 'classical' MES and scMET models. The most active compounds, (4R,8aR)-3a, and (4S,8aS)-6 displayed median effective doses (ED50) of 47.90 and 126.19 mg/kg, respectively, for the 6 Hz test.
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1 Str., 02-097 Warszawa, Poland. maciej.dawidowski@wum.edu.pl.
authors.forename: Maciej
authors.initials: M
authors.lastname: Dawidowski
authors.affiliation: Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warszawa, Poland. lewandowski.w@o2.pl.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Lewandowski
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1 Str., 02-097 Warszawa, Poland. jadwiga.turlo@wum.edu.pl.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Turło
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004827:Epilepsy / Q000188:drug therapy*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D011719:Pyrazines