Synthesis and pharmacological evaluation of a second generation of pyridothiadiazine 1,1-dioxides acting as AMPA potentiators.
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.
Francotte
Pierre
P
Drug Research Center, Laboratory of Medicinal Chemistry, University of Liège, Av. de l'Hôpital, 1, B36, 4000 Liège, Belgium. Pierre.Francotte@ulg.ac.be
de Tullio
Pascal
P
Podona
Tchao
T
Diouf
Ousmane
O
Fraikin
Pierre
P
Lestage
Pierre
P
Danober
Laurence
L
Thomas
Jean-Yves
JY
Caignard
Daniel-Henri
DH
Pirotte
Bernard
B
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*
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