2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2023 Mar 15;250:115221. doi: 10.1016/j.ejmech.2023.115221.
Eric Goffin 1,  Pierre Fraikin 1,  Dayana Abboud 2,  Pascal de Tullio 1,  Caroline Beaufour 3,  Iuliana Botez 3,  Julien Hanson 4,  Laurence Danober 3,  Pierre Francotte 1,  Bernard Pirotte 5
Affiliations

Affiliations

  • 1 Center for Interdisciplinary Research on Medicines (CIRM) - Laboratory of Medicinal Chemistry, University of Liège, Avenue Hippocrate 15 (B36), B-4000, Liège, Belgium.
  • 2 Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, Avenue Hippocrate 1/11 (B34), B-4000, Liège, Belgium.
  • 3 Institut de Recherches Servier, 125 Chemin de Ronde, F-78290, Croissy-sur-Seine, France.
  • 4 Center for Interdisciplinary Research on Medicines (CIRM) - Laboratory of Medicinal Chemistry, University of Liège, Avenue Hippocrate 15 (B36), B-4000, Liège, Belgium; Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, Avenue Hippocrate 1/11 (B34), B-4000, Liège, Belgium.
  • 5 Center for Interdisciplinary Research on Medicines (CIRM) - Laboratory of Medicinal Chemistry, University of Liège, Avenue Hippocrate 15 (B36), B-4000, Liège, Belgium. Electronic address: b.pirotte@uliege.be.
PMID: 36863228 DOI: 10.1016/j.ejmech.2023.115221
Abstract

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.

Keywords

1,2,4-Benzothiadiazine 1,1-dioxides; Cognitive enhancer; Ionotropic glutamate receptors; N-Mono/difluoromethyl-substituted compounds; Positive allosteric modulator.

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