7w0g
From Proteopedia
Human PPAR delta ligand binding domain in complex with a synthetic agonist H11
Structural highlights
Function[PPARD_HUMAN] Ligand-activated transcription factor. Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-linoleic acid and eicosapentanoic acid. Once activated by a ligand, the receptor binds to promoter elements of target genes. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the acyl-CoA oxidase gene. Decreases expression of NPC1L1 once activated by a ligand.[1] [2] Publication Abstract from PubMedPeroxisome proliferator-activator receptors alpha/delta (PPARalpha/delta) are regarded as potential therapeutic targets for nonalcoholic steatohepatitis (NASH). However, PPARalpha/delta dual agonist GFT-505 exhibited poor anti-NASH effects in a phase III clinical trial, probably due to its weak PPARalpha/delta agonistic activity and poor metabolic stability. Other reported PPARalpha/delta dual agonists either exhibited limited potency or had unbalanced PPARalpha/delta agonistic activity. Herein, we report a series of novel triazolone derivatives as PPARalpha/delta dual agonists. Among them, compound H11 exhibited potent and well-balanced PPARalpha/delta agonistic activity (PPARalpha EC50 = 7.0 nM; PPARdelta EC50 = 8.4 nM) and a high selectivity over PPARgamma (PPARgamma EC50 = 1316.1 nM) in PPAR transactivation assays. The crystal structure of PPARdelta in complex with H11 revealed a unique PPARdelta-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. Design, Synthesis, and Biological Evaluation of Triazolone Derivatives as Potent PPARalpha/delta Dual Agonists for the Treatment of Nonalcoholic Steatohepatitis.,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 J Med Chem. 2022 Jan 21. doi: 10.1021/acs.jmedchem.1c02002. PMID:35060744[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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