Discovery, synthesis and SAR of azinyl- and azolylbenzamides antagonists of the P2X7 receptor

Regulation of the T Cell Response by CD39

“…Thus, it is tempting to speculate that molecules that increase AHR expression or activity, such as melatonin (62) or AhR agonists (68) might be exploited to increase CD39 expression in Tr1 cells and consequently, the suppressive function and stability. Together with specific P2rX7 inhibitors (69), these molecules might offer new avenues for the development of Tr1 cell-based immunotherapies.…”

“…The administration of exogenous CD39, either as a recombinant protein, purified protein or in nanoparticles might provide a new approach to limit inflammation. This therapeutic approach is likely to be more efficient than existing strategies aimed at blocking P2X (69) or other receptors because of the ability not only to limit eATP signaling, but also to promote the generation of anti-inflammatory adenosine. Conversely, based on the expression of CD39 by exhausted T cells, the blockade of CD39 with small molecules or specific biological reagents such as monoclonal antibodies might provide a new approach to unleash protective immune responses in the context of chronic infections or tumor immunotherapy.…”

Structure-based identification and characterisation of structurally novel human P2X7 receptor antagonists

“…It plays an important role in a diversity of conditions associated with tissue damage or inflammation including chronic pain, rheumatoid arthritis and age-related macular degeneration, making the P2X7R an attractive therapeutic target [33], [38], [1]. Huge drug discovery efforts over the past few years have led to the discovery of numerous P2X7R antagonists [17], [41], [27]. Whilst clinical trials of the first two P2X7R antagonists against rheumatoid arthritis showed disappointing outcomes [26], [39], a more recent clinical trial shows promise in the therapeutic use of a P2X7R antagonist (AZD9056) in the treatment of moderate-to-severe Crohn’s disease [10].…”

P2X7 Antagonists as Potential Therapeutic Agents for the Treatment of CNS Disorders

“…The authors assert that it was the acidic nature of this ring which presumably led to a low V dss in vivo, as well as the short halflife observed [120]. The authors assert that it was the acidic nature of this ring which presumably led to a low V dss in vivo, as well as the short halflife observed [120].…”