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

Journal of Medicinal Chemistry
2022.0

Abstract

Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are regarded as potential therapeutic targets for nonalcoholic steatohepatitis (NASH). However, PPARα/δ dual agonist <b>GFT-505</b> 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 <b>H11</b> exhibited potent and well-balanced PPARα/δ agonistic activity (PPARα EC<sub>50</sub> = 7.0 nM; PPARδ EC<sub>50</sub> = 8.4 nM) and a high selectivity over PPARγ (PPARγ EC<sub>50</sub> = 1316.1 nM) in PPAR transactivation assays. The crystal structure of PPARδ in complex with <b>H11</b> revealed a unique PPARδ-agonist interaction. <b>H11</b>, which had excellent PK properties and a good safety profile, showed potent in vivo anti-NASH effects in preclinical models. Together, <b>H11</b> holds a great promise for treating NASH or other inflammatory and fibrotic diseases.

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