title: Synthesis and pharmacological evaluation of a second generation of pyridothiadiazine 1,1-dioxides acting as AMPA potentiators.
abstract: Taking into account structure-activity relationships obtained with our previous series, new diversely substituted 1,2,4-pyridothiadiazine 1,1-dioxides were designed to obtain novel AMPA potentiators. The aim of this work was focused on the improvement of lipophilicity, which is well known as a critical parameter to obtain in vivo active central nervous system agents. For this purpose, two positions on the pyridine ring were privileged to insert selected groups. Among the synthesized compounds emerged 7-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-e]-[1,2,4]-thiadiazine 1,1-dioxide (12d), which was evaluated in two memory tests in Wistar rats and showed cognition enhancing effects after intraperitoneal injection at doses as low as 0.3mg/kg.
authors.affiliation: Drug Research Center, Laboratory of Medicinal Chemistry, University of Liège, Av. de l'Hôpital, 1, B36, 4000 Liège, Belgium. Pierre.Francotte@ulg.ac.be
authors.forename: Pierre
authors.initials: P
authors.lastname: Francotte
authors.forename: Pascal
authors.initials: P
authors.lastname: de Tullio
authors.forename: Tchao
authors.initials: T
authors.lastname: Podona
authors.forename: Ousmane
authors.initials: O
authors.lastname: Diouf
authors.forename: Pierre
authors.initials: P
authors.lastname: Fraikin
authors.forename: Pierre
authors.initials: P
authors.lastname: Lestage
authors.forename: Laurence
authors.initials: L
authors.lastname: Danober
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Thomas
authors.forename: Daniel-Henri
authors.initials: DH
authors.lastname: Caignard
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
mesh_terms: D000818:Animals; D003981:Diazoxide / Q000737:chemistry / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D012995:Solubility; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014982:Xenopus laevis; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C534075:7-chloro-4-ethyl-3,4-dihydro-2H-pyrido(2,3-e)-(1,2,4)-thiadiazine 1,1-dioxide; D018091:Receptors, AMPA; D013829:Thiadiazines; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D003981:Diazoxide