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; Tullio, Pascal De; Beaufour, Caroline; Botez, Iuliana; Hanson, Julien; Danober, Laurence; Francotte, Pierre; Pirotte, Bernard

doi:10.1016/j.ejmech.2023.115221

Cited by 7 publications

(7 citation statements)

References 48 publications

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“…c EC50: AMPAR potentiator concentration responsible for 50% of the maximal effect (mean ± SEM (n = 3)). d Published compounds and results [27,38]; for 5 the result is given as the mean ± SEM (n) [27]. e Compound 36 tested on Xenopus oocytes (magnitude of the current induced by AMPA (10 µM) in Xenopus oocytes injected with rat cortex mRNA according to [24] expressed an EC2x value of 15.…”

Section: Accession Codementioning

confidence: 99%

“…The 2,3,4-trimethyl-substituted BTD 12 (Figure 1) was surprisingly found to be a potent AMPAR PAM in vitro, while the corresponding 2,3- and 3,4-dimethyl-substituted analogues were substantially less active [31]. Recently, compound 13 bearing a fluoromethyl group at the 2-position was found to exert better in vivo activity (improvement of cognitive functions) after oral administration in mice compared to its 2-unsubstituted analogue 3 [38].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, compound 13 bearing a fluoromethyl group at the 2-position was found to exert better in vivo activity (improvement of cognitive functions) after oral administration in mice compared to its 2-unsubstituted analogue 3 [38].…”

Section: Introductionmentioning

confidence: 99%

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Exploring thienothiadiazine dioxides as isosteric analogues of benzo- and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators

Francotte,

Bay,

Goffin

et al. 2023

Preprint

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The synthesis and biological evaluation on AMPA and kainate receptors of new examples of 3,4-dihydro-2H-1,2,4-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxides is described.The introduction of a cyclopropyl chain instead of an ethyl chain at the 4-position of the thiadiazine ring was found to dramatically improve the potentiator activity on AMPA receptors, with compound32(BPAM395) expressingin vitroactivity on AMPARs (EC2x = 0.24 µM) close to that of the reference 4-cyclopropyl-substituted benzothiadiazine dioxide10(BPAM344).Interestingly, the 4-allyl-substituted thienothiadiazine dioxide27(BPAM307) emerged as the most promising compound on kainate receptors being a more effective potentiator than the 4-cyclopropyl-substituted thienothiadiazine dioxide32and supporting the view that the 4-allyl substitution of the thiadiazine ring could be more favorable than the 4-cyclopropyl substitution to induce marked activity on kainate receptors versus AMPA receptors.The thieno-analogue36(BPAM279) of the clinically tested S18986 (11) was selected forin vivoevaluation in mice as a cognitive enhancer due to a safer profile than32after massiveper osdrug administration. Compound36was found to increase the cognition performance in mice at low doses (1 mg/kg)per ossuggesting that the compound was well absorbed after oral administration and able to reach the central nervous system.Finally, compound32was selected for co-crystallization with the GluA2-LBD (L504Y,N775S) and glutamate to examine the binding mode of thienothiadiazine dioxides within the allosteric binding site of the AMPA receptor. At the allosteric site, this compound established similar interactions as the previously reported BTD-type AMPA receptor modulators.HighlightsThe study explored AMPA/kainate receptor PAMs belonging to thienothiadiazine dioxidesThe 4-cyclopropyl-substituted compound32was the most potent AMPA receptor modulator4-Allyl substitution improved activity and selectivity for kainate receptorsThe tricyclic compound36expressed cognitive improvementin vivoin miceCompound32was co-crystallized with GluA2-LBD to examine receptor binding modeGraphical abstract

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Section: Accession Codementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exploring thienothiadiazine dioxides as isosteric analogues of benzo- and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators

Francotte,

Bay,

Goffin

et al. 2023

Preprint

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“…Due to numerous pharmacological uses, BTZ ring has been incorporated into numerous medicinal drugs. [10][11][12][13][14][15][16][17][18][19][20] Compound BTZ-1 to BTZ-10 have been described already previously. [21] All these compounds were further evaluated for their in vitro anti-cancer activity via one dose (10 À 5 M) against different cancer cell lines which was selected by the NCI and NCI did its own procedure for testing.…”

Section: Introductionmentioning

confidence: 99%

“…Hence different analogues of these marketed drugs of benzothiadiazine ( BTZ‐12 to BTZ‐20 ) (Table 1) were synthesized and evaluated for their anticancer activity against different cell lines. Due to numerous pharmacological uses, BTZ ring has been incorporated into numerous medicinal drugs [10–20] . Compound BTZ‐1 to BTZ‐10 have been described already previously [21] …”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Cytotoxic Activity of New Analogues of 4‐Substituted 1,2,4‐Benzothiadiazine‐1,1‐dioxide

Chhabra,

Shah

2023

ChemistrySelect

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A new series of 4‐benzyl analogues of 1,2,4‐benzothiadiazine‐1,1‐dioxide was synthesized. All these compounds were subsequently tested for in vitro anti‐cancer activity against cancer cell lines selected by National Cancer Institute using one dose (10−5 M), following their standard screening procedure. The new compounds were characterized by 1H NMR, 13C NMR, LCMS, and IR techniques. All the synthesized compounds showed sensitivity against tested cancer cell lines. Notably, the compound having 3‐fluoro‐4‐methoxybenzyl group on 1,2,4‐benzothiadiazine‐1,1‐dioxide ring exhibited the most promising cytotoxicity effect. It displayed a growth percentage oscillating between −32.82 % and 93.85 % on Melanoma and Breast cancer cell lines, respectively. Additionally, this compound demonstrated a significant antiproliferative effect on Leukaemia and CNS cancer cell lines. The most affected cell lines were MDA‐MB‐468 (Breast Cancer, lethality is 32.82 %) and MDA‐MB‐435 (Melanoma, −15.62 %). Other compounds in the series also demonstrated considerable antiproliferative effects on Breast cancer cell line.

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Exploring thienothiadiazine dioxides as isosteric analogues of benzo- and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators

Francotte,

Bay,

Goffin

et al. 2024

European Journal of Medicinal Chemistry

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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

Cited by 7 publications

References 48 publications

Exploring thienothiadiazine dioxides as isosteric analogues of benzo- and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators

Exploring thienothiadiazine dioxides as isosteric analogues of benzo- and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators

Synthesis and Evaluation of Cytotoxic Activity of New Analogues of 4‐Substituted 1,2,4‐Benzothiadiazine‐1,1‐dioxide

Exploring thienothiadiazine dioxides as isosteric analogues of benzo- and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators

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