Design, Synthesis, and Biological Evaluation of Triazolone Derivatives as Potent PPAR alpha/delta Dual Agonists for the Treatment of Nonalcoholic Steatohepatitis

Peroxisome proliferator-activator receptors alpha/delta (PPAR alpha/delta) are regarded as potential therapeutic targets for nonalcoholic steatohepatitis (NASH). However, PPAR alpha/delta dual agonist GFT-505 exhibited poor anti-NASH effects in a phase III clinical trial, probably due to its weak PPAR alpha/delta agonistic activity and poor metabolic stability. Other reported PPAR alpha/delta dual agonists either exhibited limited potency or had unbalanced PPAR alpha/delta agonistic activity. Herein, we report a series of novel triazolone derivatives as PPAR alpha/delta dual agonists. Among them, compound H11 exhibited potent and well-balanced PPAR alpha/delta agonistic activity (PPAR alpha EC50 = 7.0 nM; PPAR delta EC50 = 8.4 and a high selectivity over PPAR gamma (PPAR gamma EC50 = 1316.1 nM) in PPAR transactivation assays. The crystal structure of PPAR6 in complex with H11 revealed a unique PPAR delta-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.