Article (Scientific journals)
New insights in the development of positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides: Introduction of (mono/difluoro)methyl groups at the 2-position of the thiadiazine ring.
Goffin, Eric; Fraikin, Pierre; Abboud, Dayana et al.
2023In European Journal of Medicinal Chemistry, 250, p. 115221
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Keywords :
1,2,4-Benzothiadiazine 1,1-dioxides; Cognitive enhancer; Ionotropic glutamate receptors; N-Mono/difluoromethyl-substituted compounds; Positive allosteric modulator; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Receptors, AMPA; Thiadiazines; Benzothiadiazines; Thiazides; Mice; Animals; Benzothiadiazines/pharmacology; Benzothiadiazines/chemistry; Allosteric Regulation; Receptors, AMPA/metabolism; Thiadiazines/pharmacology; Thiadiazines/chemistry; Pharmacology; Drug Discovery; Organic Chemistry; General Medicine
Abstract :
[en] Positive allosteric modulators of the AMPA receptors (AMPAR PAMs) have been proposed as new drugs for the management of various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, attention deficit hyperactivity disorder, depression, and schizophrenia. The present study explored new AMPAR PAMs belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides (BTDs) characterized by the presence of a short alkyl substituent at the 2-position of the heterocycle and by the presence or absence of a methyl group at the 3-position. The introduction of a monofluoromethyl or a difluoromethyl side chain at the 2-position instead of the methyl group was examined. 7-Chloro-4-cyclopropyl-2-fluoromethyl-3,4-dihydro-4H-1,2,4-benzothiadiazine 1,1-dioxide (15e) emerged as the most promising compound associating high in vitro potency on AMPA receptors, a favorable safety profile in vivo and a marked efficacy as a cognitive enhancer after oral administration in mice. Stability studies in aqueous medium suggested that 15e could be considered, at least in part, as a precursor of the corresponding 2-hydroxymethyl-substituted analogue and the known AMPAR modulator 7-chloro-4-cyclopropyl-3,4-dihydro-4H-1,2,4-benzothiadiazine 1,1-dioxide (3) devoid of an alkyl group at the 2-position.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Goffin, Eric ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Fraikin, Pierre ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Abboud, Dayana  ;  Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Molecular Pharmacology
De Tullio, Pascal ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Beaufour, Caroline;  Institut de Recherches Servier, 125 Chemin de Ronde, F-78290, Croissy-sur-Seine, France
Botez, Iuliana;  Institut de Recherches Servier, 125 Chemin de Ronde, F-78290, Croissy-sur-Seine, France
Hanson, Julien  ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Danober, Laurence;  Institut de Recherches Servier, 125 Chemin de Ronde, F-78290, Croissy-sur-Seine, France
Francotte, Pierre  ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Pirotte, Bernard ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Language :
English
Title :
New insights in the development of positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides: Introduction of (mono/difluoro)methyl groups at the 2-position of the thiadiazine ring.
Publication date :
15 March 2023
Journal title :
European Journal of Medicinal Chemistry
ISSN :
0223-5234
eISSN :
1768-3254
Publisher :
Elsevier Masson s.r.l., France
Volume :
250
Pages :
115221
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
Servier [FR]
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Funding text :
This study was supported in part by a grant from Servier and the National Fund for Scientific Research (F.N.R.S., Belgium) from which J. Hanson is a Senior Research associate and P. de Tullio is a Research Director. The technical assistance of S. Counerotte is gratefully acknowledged.
Available on ORBi :
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