Discovery of novel AdipoRon analogues as potent anti-inflammatory agents against nonalcoholic steatohepatitis

Abstract

Nonalcoholic steatohepatitis (NASH) is a rising public health burden, and there is a lack of effective therapeutic drugs in clinical practice. Sustained hepatic inflammation is considered as the key histopathological feature and dangerous fact for NASH. Different causes vary from one NASH patient to another, while sustained hepatic inflammation affects all NASH patients. AdipoRon is the first small-molecule AdipoR agonist, exerting antidiabetic and anti-inflammatory effect. In order to find novel AdipoRon analogues with more potent anti-inflammatory activity, we designed, synthesized and biologically evaluated 32 analogues. Among them, Q7 exerted potent anti-inflammatory activity and less cytotoxicity. Q7 could dose-dependently stimulate the increasing of AMPK phosphorylation, the widely recognized downstream effector of AdipoR1 activation. In NASH model mice, Q7 showed significant anti-inflammatory, anti-fibrotic and lipid-lowering effect in mice liver, and was superior to AdipoRon. Together, Q7 holds promise for developing anti-inflammatory and anti-NASH agents.

Keywords: AdipoRon; Analogues; Anti-inflammatory; Nonalcoholic steatohepatitis.