Design, synthesis, and biological evaluation of deuterated indolepropionic acid derivatives as novel long-acting pan PPARα/γ/δ agonists.

Metabolic syndrome is a complex disease with diverse symptoms, but current pharmacological interventions have limited efficacy. Indeglitazar, a pan-agonist targeting the three-peroxisome proliferator activated receptors (PPAR), exhibits significant therapeutic effects on both diabetic and fatty liver animal models. However, its short half-life limits the in vivo efficacy, which might be attributed to the ß-oxidation of indolepropionic acid at Indeglitazar. To overcome this metabolic instability, two deuterium atoms were introduced to the α-position of indolepropionic acid to block the ß-oxidation. In this study, several deuterated derivatives were found to sustain PPARs activity and extend the half-life of liver microsomes. In oral glucose tolerance tests, I-1 exhibited the strongest glucose-lowering effect on ob/ob mice in this series. In db/db mice, I-1 reduced lipid levels, liver steatosis and promoted UCP1 expression in white adipose tissue. Mechanistic studies further revealed that I-1 exerts stronger effects than Indeglitazar on the regulation of genes related to lipid metabolism, mitochondrial function, and oxidative stress. Furthermore, I-1 significantly reduced liver steatosis, hepatocellular ballooning, inflammation, and fibrosis in NASH model induced by HFD + CCl4, and even exerted better therapeutic effect than that of Indeglitazar. With the above attractive efficacy, deuterated derivative I-1 is considered as a promising treatment for metabolic syndrome.

Pharmacokinetic Interaction of Chiglitazar with CYP3A4 Inducer or Inhibitor: An Open-Label, Sequential Crossover, Self-Control, 3-Period Study in Healthy Chinese Volunteers.

Chiglitazar, a pan agonist of non-thiazolidinedione peroxisome proliferator-activated receptor, has the potential to regulate blood sugar, improve lipid metabolism, and reduce cardiovascular complications. This study aimed to examine the effect of cytochrome P450 (CYP) 3A4 inhibitors/inducers on the in vivo metabolism of chiglitazar and provide a reference for the clinical combination use of chiglitazar. A single-center, open-label, sequential crossover, and self-control study was carried out in 24 healthy subjects to determine the pharmacokinetics of chiglitazar dosed with and without CYP3A4 inhibitors and inducers. The findings showed that the CYP3A4 inhibitor itraconazole had no apparent pharmacokinetic drug interaction with chiglitazar, whereas rifampicin did. When combined with rifampicin after continuous dosing, chiglitazar exposure was not theoretically reduced but increased compared to a single dose of chiglitazar. The possible explanation may be the transporters of bile salt export pump, but this needs to be confirmed. The safety of chiglitazar in single or combination doses was well tolerated. The findings of this study provide a basis for clinical combinations of chiglitazar with CYP3A4 inhibitors or inducers.

A chemoinformatics search for peroxisome proliferator-activated receptors ligands revealed a new pan-agonist able to reduce lipid accumulation and improve insulin sensitivity.

The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the regulation of the metabolic homeostasis and therefore represent valuable therapeutic targets for the treatment of metabolic diseases. The development of more balanced drugs interacting with PPARs, devoid of the side-effects showed by the currently marketed PPARγ full agonists, is considered the major challenge for the pharmaceutical companies. Here we present a chemoinformatics search approach for new ligands that let us identify a novel PPAR pan-agonist with a very attractive activity profile being able to reduce lipid accumulation and improve insulin sensitivity. This compound represents, therefore, the potential lead of a new class of drugs for treatment of dyslipidemic type 2 diabetes.

Efficacy and safety of chiglitazar, a novel peroxisome proliferator-activated receptor pan-agonist, in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, phase 3 trial (CMAP).

Chiglitazar (Carfloglitazar) is a novel non-thiazolidinedione (TZD) structured peroxisome proliferator-activated receptor (PPAR) pan-agonist that has shown promising effects on glycemic control and lipid regulation in patients with type 2 diabetes in previous clinical studies. This randomized phase 3 trial aimed to compare the efficacy and safety of chiglitazar with placebo in patients with type 2 diabetes with insufficient glycemic control by strict diet and exercise alone. Eligible patients were randomly assigned to receive chiglitazar 32 mg (n = 167), chiglitazar 48 mg (n = 166), or placebo (n = 202) once daily. The primary endpoint was the change in glycosylated hemoglobin A1c (HbA1c) at week 24 with superiority of chiglitazar over placebo. The results showed that both chiglitazar 32 and 48 mg resulted in significant and clinically meaningful reductions in HbA1c, and placebo-adjusted estimated treatment differences at week 24 for chiglitazar 32 and 48 mg were -0.87% (95% confidential interval (CI): -1.10 to -0.65; P < 0.0001) and -1.05% (95% CI: -1.29 to -0.81; P < 0.0001), respectively. Secondary efficacy parameters including glycemic control, insulin sensitivity and triglyceride reduction were also significantly improved in the chiglitazar groups. The overall frequency of adverse events and study discontinuation attributable to adverse events were similar among the groups. Low incidences of mild edema and body weight gain were reported in the chiglitazar dose groups. The results from this phase 3 trial demonstrated that the PPAR pan-agonist chiglitazar possesses an overall good efficacy and safety profile in patients with type 2 diabetes inadequately controlled with lifestyle interventions, thereby providing adequate supporting evidence for using this PPAR pan-agonist as a treatment option for type 2 diabetes.

Chiglitazar monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomized, double-blind, phase 3 trial (CMAS).

Chiglitazar (Carfloglitazar) is a novel peroxisome proliferator-activated receptor (PPAR) pan-agonist that has shown promising effects on glycemic control and lipid regulation in patients with type 2 diabetes. In this randomized phase 3 trial, we compared the efficacy and safety of chiglitazar with sitagliptin in patients with type 2 diabetes who had insufficient glycemic control despite a strict diet and exercise regimen. Eligible patients were randomized (1:1:1) to receive chiglitazar 32 mg (n = 245), chiglitazar 48 mg (n = 246), or sitagliptin 100 mg (n = 248) once daily for 24 weeks. The primary endpoint was the change in glycosylated hemoglobin A1C (HbA1c) from baseline at week 24 with the non-inferiority of chiglitazar over sitagliptin. Both chiglitazar and sitagliptin significantly reduced HbA1c at week 24 with values of -1.40%, -1.47%, and -1.39% for chiglitazar 32 mg, chiglitazar 48 mg, and sitagliptin 100 mg, respectively. Chiglitazar 32 and 48 mg were both non-inferior to sitagliptin 100 mg, with mean differences of -0.04% (95% confidential interval (CI) -0.22 to 0.15) and -0.08% (95% CI -0.27 to 0.10), respectively. Compared with sitagliptin, greater reduction in fasting and 2-h postprandial plasma glucose and fasting insulin was observed with chiglitazar. Overall adverse event rates were similar between the groups. A small increase in mild edema in the chiglitazar 48 mg group and slight weight gain in both chiglitazar groups were reported. The overall results demonstrated that chiglitazar possesses good efficacy and safety profile in patients with type 2 diabetes inadequately controlled with lifestyle interventions, thereby providing adequate supporting evidence for using this PPAR pan-agonist as a treatment option for type 2 diabetes.

A PPAR Pan Agonist, MHY2013 Alleviates Age-Related Hepatic Lipid Accumulation by Promoting Fatty Acid Oxidation and Suppressing Inflammation.

Nonalcoholic fatty liver disease (NAFLD) is frequently observed in obese and aged individuals. Peroxisome proliferator-activated receptors (PPARs) play a role in regulating hepatic lipid accumulation, a hallmark of NAFLD development. A PPAR pan agonist, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013) has been shown to prevent fatty liver formation and insulin resistance in obese mice (db/db) model. However, the beneficial effects of MHY2013 in aged model remain unknown. In this study, we investigated whether MHY2013 alleviates hepatic lipid accumulation in aged Sprague-Dawley (SD) rats. We confirmed that MHY2013 increased the activities of three PPAR subtypes in HepG2 cells using luciferase assay. When administered orally in aged SD rats, MHY2013 markedly decreased the hepatic triglyceride levels without changes in body weight. Regarding underlying mechanisms, MHY2013 increased the mRNA levels of lipid oxidation-related genes, including carnitine palmitoyltransferase 1 (CPT1) and peroxisomal acyl-CoA oxidase 1 (ACOX1), without apparent change in the mRNA expression of lipogenesis-related genes. Furthermore, MHY2013 significantly increased systemic fibroblast growth factor 21 (FGF21) and adiponectin levels and suppressed inflammatory mRNA expression in the liver. In conclusion, MHY2013 alleviated age-related hepatic lipid accumulation, in part by upregulating ß-oxidation signaling and suppressing inflammation in the liver. Therefore, MHY2013 is a potential pharmaceutical agent for treating age-related hepatic lipid accumulation.

Physiological characterization of a novel PPAR pan agonist, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013).

Recently, agonists targeting multiple peroxisome proliferator-activated receptors (PPARs) have been developed to improve metabolic disorders and minimize the side effects of selective PPAR agonists such as weight gain and dyslipidemia. We newly synthesized six 2-methyl-2-(o-tolyloxy)propanoic acid derivatives based on the structure of a well-known PPAR pan agonist, bezafibrate. Of six compounds, MHY2013 was screened as the strongest activator of three PPAR subtypes based on protein docking simulation and luciferase assays. When treated orally in db/db mice, MHY2013 ameliorated obesity-induced insulin resistance, dyslipidemia, and hepatic steatosis without changes of the body weight and levels of liver and kidney injury markers. MHY2013 decreased the serum triglyceride and fatty acid levels, which is associated with an increase in fatty acid oxidation signaling in the liver and thermogenic signaling on white adipose tissue, respectively. Furthermore, MHY2013 markedly increased serum levels of insulin-sensitizing hormones including fibroblast growth factor 21 (FGF21) and adiponectin. In conclusion, this study suggests that, MHY2013 is a novel PPAR pan agonist that improves obesity-induced insulin resistance, dyslipidemia and hepatic steatosis and elevates insulin-sensitizing hormones in the blood.