Pyrazole derivatives as potent inhibitors of c-Jun N-terminal kinase: Synthesis and SAR studies

A series of pyrazole amides was synthesized and screened for JNK-1 inhibitory and anti-inflammatory activity. Docking study was also performed. Mitogen activated protein kinases including c-Jun N-terminal kinase play an indispensable role in inflammatory diseases. Investigation of reported JNK-1 inhibitors indicated that diverse heterocyclic compounds bearing an amide group rendered potent JNK-1 inhibitory activity which prompted us to synthesize new JNK-1 inhibitors containing a pyrazole heterocyclic group. A DABCO mediated 1,3-dipolar cycloaddition reaction in neat resulted in pyrazole carboxylic acid which was converted to desired amides. Upon confirmation of the structures, all the compounds were screened for JNK-1 inhibitory activity and in vivo anti-inflammatory activity. Several synthesized analogues have exhibited JNK-1 inhibitory activity less than 10μM, in particular compounds 9c, 10a and 10d were found to be potent among all the compounds.