Positive Allosteric Modulators of 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors Belonging to 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-pyridothiadiazine Dioxides and Diversely Chloro-Substituted 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides
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Positive Allosteric Modulators of 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors Belonging to 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-pyridothiadiazine Dioxides and Diversely Chloro-Substituted 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides. / Francotte, Pierre; Nørholm, Ann-Beth; Deva, Taru; Olsen, Lars; Frydenvang, Karla; Goffin, Eric; Fraikin, Pierre; de Tullio, Pascal; Challal, Sylvie; Thomas, Jean-Yves; Iop, Fabrice; Louis, Caroline; Botez-Pop, Iuliana; Lestage, Pierre; Danober, Laurence; Kastrup, Jette Sandholm Jensen; Pirotte, Bernard.
In: Journal of Medicinal Chemistry, Vol. 57, No. 22, 26.11.2014, p. 9539-53.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Positive Allosteric Modulators of 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors Belonging to 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-pyridothiadiazine Dioxides and Diversely Chloro-Substituted 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides
AU - Francotte, Pierre
AU - Nørholm, Ann-Beth
AU - Deva, Taru
AU - Olsen, Lars
AU - Frydenvang, Karla
AU - Goffin, Eric
AU - Fraikin, Pierre
AU - de Tullio, Pascal
AU - Challal, Sylvie
AU - Thomas, Jean-Yves
AU - Iop, Fabrice
AU - Louis, Caroline
AU - Botez-Pop, Iuliana
AU - Lestage, Pierre
AU - Danober, Laurence
AU - Kastrup, Jette Sandholm Jensen
AU - Pirotte, Bernard
PY - 2014/11/26
Y1 - 2014/11/26
N2 - Two 4-ethyl-substituted pyridothiadiazine dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-benzothiadiazine 1,1-dioxides. The "8-aza" compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising benzothiadiazine dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood-brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg.
AB - Two 4-ethyl-substituted pyridothiadiazine dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-benzothiadiazine 1,1-dioxides. The "8-aza" compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising benzothiadiazine dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood-brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg.
KW - Allosteric Site
KW - Animals
KW - Benzothiadiazines
KW - Calorimetry
KW - Chemistry, Pharmaceutical
KW - Crystallography, X-Ray
KW - Cyclic S-Oxides
KW - Dimerization
KW - Drug Design
KW - Electrophysiology
KW - Hippocampus
KW - Humans
KW - Hydrogen
KW - Kinetics
KW - Mice
KW - Oxides
KW - Propionates
KW - Protein Binding
KW - Rats
KW - Rats, Wistar
KW - Receptors, AMPA
KW - Temperature
KW - Thermodynamics
KW - Thiadiazines
U2 - 10.1021/jm501268r
DO - 10.1021/jm501268r
M3 - Journal article
C2 - 25375781
VL - 57
SP - 9539
EP - 9553
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 22
ER -
ID: 138521438