Design, Synthesis, and Biological Evaluation of Triazolone Derivatives as Potent PPARα/δ Dual Agonists for the Treatment of Nonalcoholic Steatohepatitis

Peroxisome proliferator-activator
receptors α/δ (PPARα/δ)
are regarded as potential therapeutic targets for nonalcoholic steatohepatitis
(NASH). However, PPARα/δ dual agonist GFT-505 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 H11 exhibited potent and well-balanced PPARα/δ
agonistic activity (PPARα EC50 = 7.0 nM; PPARδ
EC50 = 8.4 nM) and a high selectivity over PPARγ
(PPARγ EC50 = 1316.1 nM) in PPAR transactivation
assays. The crystal structure of PPARδ in complex with H11 revealed a unique PPARδ-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.