Discovery of the First Subnanomolar PPARα/δ Dual Agonist for the Treatment of Cholestatic Liver Diseases

Abstract

Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are considered as potential drug targets for cholestatic liver diseases (CLD) via ameliorating hepatic cholestasis, inflammation, and fibrosis. In this work, we developed a series of hydantoin derivatives as potent PPARα/δ dual agonists. Representative compound V1 exhibited PPARα/δ dual agonistic activity at the subnanomolar level (PPARα EC50 = 0.7 nM; PPARδ EC50 = 0.4 nM) and showed excellent selectivity over other related nuclear receptors. The crystal structure revealed the binding mode of V1 and PPARδ at 2.1 Å resolution. Importantly, V1 demonstrated excellent pharmacokinetic (PK) properties and a good safety profile. Notably, V1 showed potent anti-CLD and antifibrotic effects in preclinical models at very low doses (0.03 and 0.1 mg/kg). Collectively, this work provides a promising drug candidate for treating CLD and other hepatic fibrosis diseases.

Organophosphorus-Catalyzed Direct Dehydroxylative Thioetherification of Alcohols with Hypervalent Organosulfur Compounds

“…After successfully establishing the application of our method, we focused on investigating the synthetic application of the present methodology in the synthesis of biologically valuable targets. Peroxisome proliferator-activated receptor (PPAR) has been a focus of our group’s interest . In 2021, Erhardt and co-workers reported that optimized compound 12 , as a PPAR agonist, exhibited promising potential in treating osteoporosis in mammals .…”

Bone mesenchymal stem cells improve cholestatic liver fibrosis by targeting ULK1 to regulate autophagy through PI3K/AKT/mTOR pathway

“…Cholestatic liver disease (CLD) is due to cholestasis caused by gallstones, parasites, etc., resulting in the accumulation of bile acid in the liver and systemic circulation. 1 During the occurrence and development of CLD, the gradual accumulation of bile acid leads to liver damage, inflammation, and fibrosis, and even develops into end-stage liver diseases such as cirrhosis and liver cancer. 2 , 3 Globally, liver cirrhosis is still a major threat to health; there is a 74.53% increase in the number of liver cirrhosis patients from 1990 to 2017.…”