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

Abstract

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.

Discovery of a Novel Macrocyclic ATP Citrate Lyase Inhibitor

“…However, it was limited by poor metabolic stability due to the hydrolysis of the ester group, which was critical for inhibitory activity. The significantly decreased inhibitory activity of compound 1e (Scheme ) proved the importance of the ester group . Considering this, the amide group was taken as an alternative (compound 1 ) since it was much more stable than the corresponding ester group.…”

“…The metabolic stability studies were performed with our previously reported method. 33 Briefly, the spiking solution containing human liver microsomes (0.75 mg/mL) was incubated in a 96-well sample plate with the compounds (1 μM) at 37 °C. The reactions were stopped at different time points (0, 5, 15, 30, 45, and 60 min).…”

“…The significantly decreased inhibitory activity of compound 1e (Scheme 1) proved the importance of the ester group. 33 Considering this, the amide group was taken as an alternative (compound 1) since it was much more stable than the corresponding ester group.…”

Research Progress of Multi-Target Drugs in the Treatment of Non-Alcoholic Steatohepatitis

“…Elafibranor (GFT505) is a PPARα/δ agonist, which can effectively improve insulin sensitivity, glucose homeostasis, and lipid metabolism, reduce inflammation, and has been considered a potential drug for NASH [27]. Cariou confirmed that elafibranor has significant effects in reducing triglycerides, fasting blood glucose, increasing high-density lipoprotein, and improving insulin resistance.…”

Enantioselective Total Synthesis of (−)-Hamigeran F and Its Rearrangement Product

“…Oxidation of (+)- 12 with oxygen using Ma’s Fe-catalyzed protocol gave (+)- 16 in 95% yield and 92% ee. Subsequently, Horner–Wadsworth–Emmons (HWE) olefination of (+)- 16 with benzyl 2-(dimethoxyphosphoryl)­acetate ( 18 ) followed by a sequence of hydrogenations catalyzed by Ir-black , and Pd/C, respectively, and selective reduction of the resulting carboxyl group with BH 3 afforded (+)- 11 in three steps with 52% yield.…”