[en] 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.
Disciplines :
Chemistry Pharmacy, pharmacology & toxicology
Author, co-author :
Francotte, Pierre ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
De Tullio, Pascal ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Podona, Tchao
Diouf, Ousmane
Fraikin, Pierre ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Lestage, Pierre; Institut de Recherches Servier
Danober, Laurence; Institut de Recherches Servier
Thomas, Jean-Yves; Institut de Recherches Servier
Caignard, Daniel-Henri; Institut de Recherches Servier
Pirotte, Bernard ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Language :
English
Title :
Synthesis and pharmacological evaluation of a second generation of pyridothiadiazine 1,1-dioxides acting as AMPA potentiators.
Dozmorov M., Li R., Abbas A.K., Hellberg F., Farre C., Huang F.S., Jilderos B., and Wigström H. Neurosci. Res. 55 (2006) 182-188
Graindorge E., Francotte P., Boverie S., de Tullio P., and Pirotte B. Curr. Med. Chem.: CNS Agents 4 (2004) 95-103
Lynch G. Curr. Opin. Pharmacol. 4 (2004) 4-11
Hashimoto K., Okamura N., Shimizu E., and Iyo M. Curr. Med. Chem.: CNS Agents 4 (2004) 147-154
Black M.D. Psychopharmacology 179 (2005) 154-163
Francotte P., de Tullio P., Fraikin P., Counerotte S., Goffin E., and Pirotte B. Recent Patents CNS Drug Discov. 1 (2006) 239-246
Lestage P., Danober L., Lockhart B., Roger A., Lebrun C., Robin J.-L., Desos P., and Cordi A. Res. Pract. Alzheimer's Dis. 6 (2002) 253-259
Phillips D., Sonnenberg J., Arai A.C., Vaswani R., Krutzik P.O., Kleisli T., Kessler M., Granger R., Lynch G., and Chamberlin A.R. Bioorg. Med. Chem. 10 (2002) 1229-1248
Francotte P., de Tullio P., Goffin E., Dintilhac G., Graindorge E., Fraikin P., Lestage P., Danober L., Thomas J.Y., Caignard D.H., and Pirotte B. J. Med. Chem. 50 (2007) 3153-3157
Pirotte B., Podona T., Diouf O., de Tullio P., Lebrun P., Dupont L., Somers F., Delarge J., Morain P., Lestage P., Lepagnol J., and Spedding M. J. Med. Chem. 41 (1998) 2946-2959
Hand E.S., and Baker D.C. Synthesis 12 (1989) 905-908
Thor D.H., and Holloway W.R. J. Comp. Physiol. Psychol. 96 (1982) 1000-1006
Ennaceur A., and Delacour J. Brain Res. 31 (1988) 47-59
Boyer J.H., and Schoen W. J. Am. Chem. Soc. 78 (1956) 423-425
Childress S.J., and McKee R.L. J. Am. Chem. Soc. 73 (1951) 3504-3505
Pirotte B., De Tullio P., Masereel B., Delarge J., Lepagnol J., and Renard P. Eur. Pat. Appl. (1994) EP618209A1
