The Role of Pyrazolo[3,4-d]pyrimidine-Based Kinase Inhibitors in The Attenuation of CCl4-Induced Liver Fibrosis in Rats

Abstract

Liver Fibrosis can be life-threatening if left untreated as it may lead to serious, incurable complications. The common therapeutic approach is to reverse the fibrosis while the intervention is still applicable. Celecoxib was shown to exhibit some antifibrotic properties in the induced fibrotic liver in rats. The present study aimed to investigate the possible antifibrotic properties in CCl4-induced liver fibrosis in male Sprague–Dawley rats compared to celecoxib of three novel methoxylated pyrazolo[3,4-d]pyrimidines. The three newly synthesized compounds were proved to be safe candidates. They showed a therapeutic effect against severe CCl4-induced fibrosis but at different degrees. The three compounds were able to partially reverse hepatic architectural distortion and reduce the fibrotic severity by showing antioxidant properties reducing MDA with increasing GSH and SOD levels, remodeling the extracellular matrix proteins and liver enzymes balance, and reducing the level of proinflammatory (TNF-α and IL-6) and profibrogenic (TGF-β) cytokines. The results revealed that the dimethoxy-analog exhibited the greatest activity in all the previously mentioned parameters compared to celecoxib and the other two analogs which could be attributed to the different methoxylation patterns of the derivatives. Collectively, the dimethoxy-derivative could be considered a safe promising antifibrotic candidate.