7W0G

Human PPAR delta ligand binding domain in complex with a synthetic agonist H11

Summary for 7W0G

• Entry DOI: 10.2210/pdb7w0g/pdb
• Descriptor: Peroxisome proliferator-activated receptor delta, 2-[2,6-dimethyl-4-[[5-oxidanylidene-4-[4-(trifluoromethyloxy)phenyl]-1,2,4-triazol-1-yl]methyl]phenoxy]-2-methyl-propanoic acid (3 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: 65652.04

Authors

Dai, L.,Sun, H.B.,Yuan, H.L.,Feng, Z.Q. (deposition date: 2021-11-18, release date: 2022-02-02, Last modification date: 2024-05-29)

Primary citation

Feng, Z.,Xiang, J.,Liu, H.,Li, J.,Xu, X.,Sun, G.,Zheng, R.,Zhang, S.,Liu, J.,Yang, S.,Xu, Q.,Wen, X.,Yuan, H.,Sun, H.,Dai, L.
Design, Synthesis, and Biological Evaluation of Triazolone Derivatives as Potent PPAR alpha / delta Dual Agonists for the Treatment of Nonalcoholic Steatohepatitis.
J.Med.Chem., 65:2571-2592, 2022

PubMed Abstract: Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are regarded as potential therapeutic targets for nonalcoholic steatohepatitis (NASH). However, PPARα/δ dual agonist 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 exhibited potent and well-balanced PPARα/δ agonistic activity (PPARα EC = 7.0 nM; PPARδ EC = 8.4 nM) and a high selectivity over PPARγ (PPARγ EC = 1316.1 nM) in PPAR transactivation assays. The crystal structure of PPARδ in complex with revealed a unique PPARδ-agonist interaction. , which had excellent PK properties and a good safety profile, showed potent in vivo anti-NASH effects in preclinical models. Together, holds a great promise for treating NASH or other inflammatory and fibrotic diseases.

PubMed: 35060744
DOI: 10.1021/acs.jmedchem.1c02002

Experimental method

X-RAY DIFFRACTION (2.443 Å)