Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer's disease. The modulators bind within the dimer interface of the ligand-binding domain (LBD) and stabilize the agonist-bound conformation, thereby slowing receptor desensitization and/or deactivation. Here we describe the synthesis and pharmacological testing at GluA2 of a new generation of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. The most potent modulator 3 in complex with GluA2-LBD-L483Y-N754S was subjected to structural analysis by X-ray crystallography, and the thermodynamics of binding was studied by isothermal titration calorimetry. Compound 3 binds to GluA2-LBD-L483Y-N754S with a Kd of 0.35 μM (ΔH = -7.5 kcal/mol and -TΔS = -1.3 kcal/mol). This is the first time that submicromolar binding affinity has been achieved for this type of positive allosteric modulator. The major structural factor increasing the binding affinity of 3 seems to be interactions between the cyclopropyl group of 3 and the backbone of Phe495 and Met496.

Ticagrelor reversibly inhibits the platelet adenosine diphosphate P2Y 12 receptor (P2Y 12). 1 It is approved for prevention of cardiovascular events in patients with atherosclerotic cardiovascular disease and shows evidence of superior clinical performance compared with other P2Y 12 inhibitors. A post hoc analysis of the Comparison of Ticagrelor (AZD6140) and Clopidogrel in Patients With Acute Coronary Syndrome (PLATO) trial 2 revealed that patients treated with ticagrelor had a lower risk of infection-related death than those treated with clopidogrel bisulfate. 3 More recently, in the Targeting Platelet-Leukocyte Aggregates in Pneumonia With Ticagrelor (XANTHIPPE) study, ticagrelor was associated with improved lung function in patients hospitalized for pneumonia. 4 We therefore questioned whether ticagrelor or its metabolites could possess antimicrobial properties. Methods | Tic agrelor and its major metabolites (M5 AR-C133913, M7, M8 AR-C124910) 5 were synthetized and tested in time-kill assays against gram-positive methicillinresistant Staphylococcus epidermidis RP62A (MRSE) (ATCC 35984); methicillin-sensitive Staphylococcus aureus (MSSA) (ATCC 25904, ATCC 6538); glycopeptide intermediate S aureus (GISA) Mu-50 (ATCC 700699); methicillin-resistant S aureus (MRSA) (ATCC BAA-1556); Enterococcus faecalis (ATCC 29212); vancomycin-resistant E faecalis (VRE) (ATCC BAA-2365); and Streptococcus agalactiae (ATCC 12386) and against gram-negative Escherichia coli (ATCC 8739) and Pseudomonas aeruginosa (PAK laboratory strain). Biofilm formation was assessed in vitro with crystal violet staining and in a mouse model of S aureus polyurethane-implant infection using Xen-29 bacteria (Perkin Elmer). Infected disks were implanted in specific pathogen-free BALB/cAnCrl mice (Charles River). The mouse protocol was approved by the ethical committee of Liège University.

In the search of a potent cognitive enhancer, a series of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been synthesized and evaluated as positive allosteric modulators of the AMPA receptors. In the present work, we focused our efforts on the insertion of mono- or polyfluoro-substituted alkyl chains at the 4-position of the thiadiazine ring in an attempt to enhance the pharmacokinetic behavior of previously described compounds. Among all the described compounds, 7-chloro-4-(2-fluoroethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, 12b, was shown to exert a strong activity on AMPA receptors in vitro and a marked cognitive-enhancing effect in vivo after oral administration to Wistar rats. Considering its in vivo activity, the metabolic degradation of 12b was studied and compared to that of its nonfluorinated analogue 9b. Taken together, results of this study clearly validated the positive impact of the fluorine atom on the alkyl chain at the 4-position of benzothiadiazine dioxides on activity and metabolic stability.

A series of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been synthesized and evaluated as potentiators of AMPA receptors. Attention was paid to the impact of the substituent introduced at the 7-position of the heterocycle. The biological evaluation was achieved by measuring the AMPA current in rat cortex mRNA-injected Xenopus oocytes. The most potent compound, 4-ethyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (12a) was found to be active in an object recognition test in rats demonstrating cognition enhancing effects in vivo after oral administration.