Showing papers by "Pascal De Tullio published in 2014"

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.

Abstract: 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.

Composition of cyclodextrin with budesonide derivatives for treatment and prevention of pulmonary inflammatory disease

Abstract: A pharmaceutical composition for use in the therapeutic and/or prevention treatment of pulmonary inflammatory disease, comprising a cyclodextrin compound and a budesonide derivative of formula I

Activation of the calcium-sensing receptor before renal ischemia/reperfusion exacerbates kidney injury in mouse

Abstract: Activation of the calcium-sensing receptor (CaSR) by ischemia/reperfusion (I/R) favours apoptosis in cardiomyocytes, hepatocytes and neurons. Its role in renal I/R is unknown. We investigated the impact of pharmacological preactivation of the CaSR on kidney structure and function in a murine model of bilateral renal 30-min ischemia and 48-hour reperfusion, and in a 6-year cohort of kidney transplant recipients (KTR). C57BL/6J mice were administered daily with CaSR agonist, R-568, or with vehicle for 48 hours. Evaluation of serum urea and creatinine levels, renal histology and urine metabolome by nuclear magnetic resonance showed that R-568 was not nephrotoxic per se. Following I/R, serum urea and creatinine levels increased higher in R-568-treated animals than in controls. Jablonski’s score was significantly greater in R-568-treated kidneys, which showed a higher rate of cell proliferation and apoptosis in comparison to controls. Next, we retrospectively identified 36 patients (10.7% of our cohort) who were treated by CaSR agonist, cinacalcet, at the time of kidney transplantation (KTx). After matching these to 61 KTR upon type of donor, cold ischemic time, residual diuresis, and donor age, we observed that delayed graft function, i.e. need for dialysis in the first week after KTx, occurred in 42 and 23% of cinacalcet-treated and control groups, respectively (p≤0.05). These data suggest that pharmacological preactivation of the CaSR before renal I/R exacerbates kidney injury.