Rational Design, Synthesis And Evaluation Of Novel C6-Bicycloalkaneimidazole Containing Imidazo[1,2-B]Pyridazines For Ask1 Inhibition

Apoptosis signal-regulating kinase 1 (ASK1) is a member of mitogen-activated protein kinase kinase kinase (MAP3K) family that involves downstream phosphorylation of MAP kinases, c-Jun N-terminal kinases, and p38 MAP kinases. ASK1 inhibitors could possibly be beneficial for ameliorating the development and progression of diseases. Especially, ASK1 has been of interest as one of therapeutic targets for nonalcoholic fatty liver disease as the most common chronic liver diseases including simple steatosis and nonalcoholic steatohepatitis. In this manuscript, novel ASK1 inhibitor lead KTA-29 which has an imidazo[1,2-b]pyridazine core with novel C6-bicycloheptaneimidazole is disclosed. With the novel imidazo[1,2-b]pyridazine core, structure-activity-relationship study for ASK1 potency is described and KTA-29 affinity toward ASK1 with molecular modeling study is explained.