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Publication Abstract from PubMed

Peroxisome proliferator-activator receptors alpha/delta (PPARalpha/delta) 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 PPARalpha/delta dual agonists. Representative compound V1 exhibited PPARalpha/delta dual agonistic activity at the subnanomolar level (PPARalpha EC(50) = 0.7 nM; PPARdelta EC(50) = 0.4 nM) and showed excellent selectivity over other related nuclear receptors. The crystal structure revealed the binding mode of V1 and PPARdelta at 2.1 A 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.

Discovery of the First Subnanomolar PPARalpha/delta Dual Agonist for the Treatment of Cholestatic Liver Diseases.,Feng Z, Xiang J, Sun G, Liu H, Wang Y, Liu X, Feng J, Xu Q, Wen X, Yuan H, Sun H, Dai L J Med Chem. 2023 Jun 8;66(11):7331-7354. doi: 10.1021/acs.jmedchem.2c02123. Epub , 2023 May 27. PMID:37243609^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.