Development of cognitive enhancers acting through AMPA potentiation: design of novel thienothiadiazine 1,1-dioxides

Poster (2010, September 08)

Coupling of Liquid Chromatography/Tandem Mass Spectrometry and Liquid Chromatography/Solid-Phase Extraction/NMR Techniques for the Structural Identification of Metabolites following In Vitro Biotransformation of SUR1-Selective ATP-Sensitive Potassium Channel Openers

in Drug Metabolism and Disposition : The Biological Fate of Chemicals (2010), 38(2), 232-240

SUR1-selective ATP-sensitive potassium channel openers (PCOs) have been shown to be of clinical value for the treatment of several metabolic disorders, including type I and type II diabetes, obesity and ... [more ▼]

SUR1-selective ATP-sensitive potassium channel openers (PCOs) have been shown to be of clinical value for the treatment of several metabolic disorders, including type I and type II diabetes, obesity and hyperinsulinemia. Taking into account these promising therapeutic benefits, different series of 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides structurally related to diazoxide were developed. In view of the lead optimisation process of the series, knowledge of ADMET parameters, and more particularly the metabolic fate of these compounds, is a fundamental requirement. For such a purpose, two selected promising compounds (BPDZ 73 and BPDZ 157) were incubated in the presence of phenobarbital-induced rat liver microsomes to produce expected mammal in vivo phase I metabolites. The resulting major metabolites were then analysed by both MS and NMR in order to completely elucidate their chemical structures. The two compounds were also further incubated in the presence of non-treated rats and human microsomes in order to compare the metabolic profiles. In the present study, the combined use of an exact mass LC-MS/MS platform and a LC-SPE-NMR system allowed the clarification of some unresolved structural assessments in the accurate chemical structure elucidation process of the selected PCOs drugs. These results greatly help the optimization of the lead compounds. [less ▲]

Chloro-Substituted 3-Alkylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxides as ATP-Sensitive Potassium Channel Activators: Impact of the Position of the Chlorine Atom on the Aromatic Ring on Activity and Tissue Selectivity

in Journal of Medicinal Chemistry (2010), 53

New Biological Investigations on 3-Bromophenyl 6-Acetoxymethyl-2-oxo-2H-1-Benzopyran-3-Carboxylate as Anti-angiogenic Agent

in Drug Development Research (2010), 71

The development of blood vessels inside tumors is required to provide the nutrients and oxygen needed for tumor growth and to allow the spread of cancer cells at a distance to form metastasis ... [more ▼]

The development of blood vessels inside tumors is required to provide the nutrients and oxygen needed for tumor growth and to allow the spread of cancer cells at a distance to form metastasis. Angiogenesis is also implicated in ocular diseases like age-related macular degeneration. The present work describes the potential anti-angiogenic properties of a coumarinic derivative, 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (IK9), previously described as a potent inhibitor of HT 1080 fibrosarcoma cell invasion in vitro and tumor growth in vivo. In vivo, ex vivo, and in vitro models were used to delineate the anti-angiogenic properties of IK9. The anti-angiogenic effect of IK9 was demonstrated in vivo in a choroidal neovascularization mice model and additionally ex vivo in a rat aortic ring assay where it was more active than the known matrix metalloproteinase inhibitor Ro 28-2653. IK9 did not affect apoptosis, proliferation, or endothelial cell invasiveness in vitro. These findings suggest a complex mechanism of action of the compound via direct or indirect effects on endothelial cell properties. This study identifies IK9 as a new potent inhibitor of angiogenesis and suggests its potential use as a therapeutic agent. [less ▲]

Preparation of cycloalkylated benzothiadiazine derivatives and their use as AMPA receptor modulators

Patent (2009)

Stabilisation métabolique par introduction d’atomes de fluor : application aux benzothiadiazine 1,1-dioxydes agissant en tant que potentialisateurs AMPA

Poster (2009, May)

Conception, synthèse et évaluation biologique de dérivés coumariniques en tant qu’agents anti-cancéreux potentiels

Poster (2009, May)

Les canaux potassiques ATP-dépendants : nouvelles cibles potentielles pour le traitement de divers troubles métaboliques

Conference (2009, February 03)

Application of Metabolomic Approaches to the Age-related Macular Degeneration (AMD)

Conference (2009, January 30)

Original cromakalim analogues as KATP channel openers

in Metabolic and Functional Research on Diabetes (2009), 2