Synthetic molecules as P2X7 receptor antagonists: A medicinal chemistry update focusing the therapy of inflammatory diseases.

Stimulation of the P2X7 receptor by extracellular adenosine 5'-triphosphate induces a series of responses in the organism, exceptionally protein cascades related to the proinflammatory process. This has made P2X7 a target for research on inflammatory diseases such as rheumatoid arthritis. Thus, the incessant search for new prototypes that aim to antagonize the action of P2X7 has been remarkable in recent decades, a factor that has already led to numerous clinical studies in humans. In this review, we present the key molecules developed over the years with potential inhibition of P2X7 and inflammation. In addition, an update with newly developed chemical classes with promising activity and results in clinical studies for human pathologies focusing on P2X7 inhibition.

Antinociceptive, anti-inflammatory and antipyretic effects of 1.5-diphenyl-1H-Pyrazole-3-carbohydrazide, a new heterocyclic pyrazole derivative.

AIMS: Heterocyclic pyrazole derivative has been described for the treatment of pain and inflammatory diseases. This study evaluated the in vivo, antinociceptive, anti-inflammatory and antipyretic effects of 1.5-diphenyl-1H-Pyrazole-3-carbohydrazide (1.5-DHP) and the in vivo or in vitro mechanism of action. MAIN METHODS: Acetic acid-induced writhing, hot-plate and formalin-induced nociception tests were used to evaluate the antinociceptive effect, while the rota-rod test was used to assess the motor activity. Croton oil-induced ear edema and carrageenan-induced peritonitis tests were used to investigate the anti-inflammatory effect of 1.5-DHP. The antipyretic effect was assessed using the LPS-induced fever model. The mechanism of action was evaluated by PGE2 and TNF-α measurement and cyclooxygenase inhibition assay. KEY FINDINGS: Oral administration (p.o.) of 1.5-DHP (1, 3, 10 mg/kg) caused a dose-related inhibition of the acetic acid-induced writhing, however the highest dose was not effective on the hot-plate and rota-rod. In the formalin-induced nociception, 1.5-DHP (10mg/kg, p.o.) inhibited only the late phase of nociception. This same dose of 1.5-DHP also reduced the croton oil-induced ear edema. 1.5-DHP (3, 10, 30 mg/kg, p.o.) produced a dose-related reduction of leukocyte migration on the carrageenan-induced peritonitis. 1.5-DHP (60 mg/kg, p.o.) reduced the fever and the increase of PGE2 concentration in the cerebrospinal fluid induced by LPS. 1.5-DHP inhibited both COXs in vitro. Finally, 1.5-DHP (10 mg/kg, p.o.) reduced the TNF-α concentration in peritoneal exudates after carrageenan injection. SIGNIFICANCE: These results indicate that 1.5-DHP produces anti-inflammatory, antinociceptive and antipyretic effects by PGE2 synthesis reduction through COX-1/COX-2 inhibition and by TNF-α synthesis/release inhibition.