Synthesis And Biological Evaluation Of 4-substituted Pyrazoles As Dual Inhibitors Of ALK5/p38α

Cancer is the second largest disease in the world,which is the important cause of human death.Morbidity and mortality of cancer are increasing year by year in China.The results of the research show that there were about 3.58 million new malignant tumors in China in 2012,of which 2.187 million were deaths and the mortality rate was as high as 61%.The clinical treatment of tumor is surgical treatment,radiotherapy and chemotherapy,among which chemotherapy is the most important treatment.However,due to the selectivity of a general chemotherapeutic drugs is low,it will inevitably damage to human body normall cells while killing cancer cells,resulting in the adverse reactions of drugs,and ultimately leading to poor efficacy and even treatment failure.Therefore,the research and development of chemotherapeutics with good selectivity and low side effects is the most important topic in cancer treatment.At present,the research and development of new anti-tumor drugs mainly focus on tarted therapy,and the selection of targets mainly focuses on kinase,receptor and protein.In recent years,the research and development of antitumor drugs targeting kinases have achieved the most outstanding results.Among them,activin receptor-like kinase 5(ALK5)is a hot target for the recent development of anti-tumor drugs.Its kinase inhibitors have also become the focus of most laboratories.ALK5 is one of the major receptors in the process of transforming growth factor-β(TGF-β)signaling,and the signal transduction pathway of transforming growth factor-beta is an important pathway to regulate tumorigenesis and development.Therefore,the research and development of an anti-tumor drug that selectively inhibits ALK5 and highly effective is the goal of our research group for this experimental study.In this paper,we found that compounds containing quinolin-4-yl and 2-phenylpyridin-4-yl moiety have strong ALK5 inhibition activity.According to the previous research of this research group,it was found that the derivatives containing pyrazole moiety showed higher ALK5 inhibition activity.Based on the combination principle and biosostere theory,two series of 3(5)-(6-methylpyridin-yl)-4-(quinolin-4-yl)pyrazoles 24a-d,25a-d,31a-d and 3(5)-(6-methylpyridin-2-yl)-4-(2-phenyl-pyridine-4-yl)pyrazoles 29a-d,30a-d,and 32a-d have been synthesized and evaluated for their ALK5 and p3 8α mitogen activated protein(MAP)kinase inhibitory activities in enzymatic assays.The preliminary results show that all the compounds possessing a quinolin-4-yl moiety,12a-d,13a-d,and 21a-d displayed better potent ALK5 inhibition(21%-100%)than those possessing a 2-phenylpyridin-4-yl one,19a-d,20a-d,and 22a-d(0%-97%)at 10 μM.The amides 12a-d(98%-100%)and 19a-d(80%-97%)showed more potent ALK5 inhibition than their respective positional isomers,13a-d(21%-83%)and 20a-d(0%-7%),respectively.In the two series of compounds,the positional isomers 13a-d and 20a-d showed weak ALK5 inhibitory activity.The results of the analysis of all compounds on the residual activity of p38α MAP kinase showed that all the target compounds except 30a-d showed good p38α inhibition at the maximum concentration of 10μM.In addition,these two series of compounds showed similar activity with ALK5 residue.In order to evaluate the ALK5 inhibitory activity and selectivity of the target compounds,we determined the IC50 values of the thioamide compounds 31a-d and 32a-d in the further activity test experiments.Compound 31c showed the most potent ALK5 and p38α inhibitory activity with IC50 values of 0.043μM and 0.063 μM in these two series,respectively.Compound 31c showed 2.8-fold and 7.7-fold more potent activity against ALK5 and p38α MAP kinase than clinical candidate,compound 17(LY-2157299),respectively.To explain the difference in inhibitory activity,molecular docking study using Discovery Studio(DS)program was performed for selected sets of compounds 31b and 32b,and it was found that the compound 31b showed better docking interaction than compound 32b in its active site.ADMET prediction of all targeted compounds showed that these compounds possess good pharmacokinetic and drug-likeness behavior.Our study suggested that compound 31c was a potential dual inhibitor of ALK5 and p38α.