8HF8

Human PPAR delta ligand binding domain in complex with a synthetic agonist V1

Summary for 8HF8

• Entry DOI: 10.2210/pdb8hf8/pdb
• Descriptor: Peroxisome proliferator-activated receptor delta, 2-[4-[[2,5-bis(oxidanylidene)-3-[4-(trifluoromethyl)phenyl]imidazolidin-1-yl]methyl]-2,6-dimethyl-phenoxy]-2-methyl-propanoic acid, octyl beta-D-glucopyranoside, ... (4 entities in total)
• Functional Keywords: complex, agonist, peroxisome proliferator-activated receptor, nuclear protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 66234.81

Authors

Dai, L.,Sun, H.B.,Yuan, H.L.,Feng, Z.Q. (deposition date: 2022-11-09, release date: 2023-09-06)

Primary citation

Feng, Z.,Xiang, J.,Sun, G.,Liu, H.,Wang, Y.,Liu, X.,Feng, J.,Xu, Q.,Wen, X.,Yuan, H.,Sun, H.,Dai, L.
Discovery of the First Subnanomolar PPAR alpha / delta Dual Agonist for the Treatment of Cholestatic Liver Diseases.
J.Med.Chem., 66:7331-7354, 2023

PubMed 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 exhibited PPARα/δ dual agonistic activity at the subnanomolar level (PPARα EC = 0.7 nM; PPARδ EC = 0.4 nM) and showed excellent selectivity over other related nuclear receptors. The crystal structure revealed the binding mode of and PPARδ at 2.1 Å resolution. Importantly, demonstrated excellent pharmacokinetic (PK) properties and a good safety profile. Notably, 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.

PubMed: 37243609
DOI: 10.1021/acs.jmedchem.2c02123

Experimental method

X-RAY DIFFRACTION (2.11 Å)