Potential Therapeutic Value of the STING Inhibitors.

The stimulator of interferon genes (STING) is a critical protein in the activation of the immune system in response to DNA. It can participate the inflammatory response process by modulating the inflammation-preferred translation program through the STING-PKR-like endoplasmic reticulum kinase (PERK)-eIF2α pathway or by inducing the secretion of type I interferons (IFNs) and a variety of proinflammatory factors through the recruitment of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) or the regulation of the nuclear factor kappa-B (NF-κB) pathway. Based on the structure, location, function, genotype, and regulatory mechanism of STING, this review summarizes the potential value of STING inhibitors in the prevention and treatment of infectious diseases, psoriasis, systemic lupus erythematosus, non-alcoholic fatty liver disease, and other inflammatory and autoimmune diseases.

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

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.

Design, Synthesis, and Biological Evaluation of Triazolone Derivatives as Potent PPARα/δ Dual Agonists for the Treatment of Nonalcoholic Steatohepatitis.

Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are regarded as potential therapeutic targets for nonalcoholic steatohepatitis (NASH). However, PPARα/δ dual agonist GFT-505 exhibited poor anti-NASH effects in a phase III clinical trial, probably due to its weak PPARα/δ agonistic activity and poor metabolic stability. Other reported PPARα/δ dual agonists either exhibited limited potency or had unbalanced PPARα/δ agonistic activity. Herein, we report a series of novel triazolone derivatives as PPARα/δ dual agonists. Among them, compound H11 exhibited potent and well-balanced PPARα/δ agonistic activity (PPARα EC50 = 7.0 nM; PPARδ EC50 = 8.4 nM) and a high selectivity over PPARγ (PPARγ EC50 = 1316.1 nM) in PPAR transactivation assays. The crystal structure of PPARδ in complex with H11 revealed a unique PPARδ-agonist interaction. H11, which had excellent PK properties and a good safety profile, showed potent in vivo anti-NASH effects in preclinical models. Together, H11 holds a great promise for treating NASH or other inflammatory and fibrotic diseases.