Discovery of novel dual PPARα/δ agonists based on benzimidazole scaffold for the treatment of non-alcoholic fatty liver disease

doi:10.1016/j.bioorg.2020.103803

Bioorganic Chemistry

Volume 99, June 2020, 103803

https://doi.org/10.1016/j.bioorg.2020.103803 Get rights and content

Highlights

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The novel dual PPARα/δ agonist was identified based on PPARα/γ/δ agonist MHY2013.
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Compound 4 exhibited high selectivity against PPARγ.
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Compound 4 formed multiple interactions with key residues of PPARα and PPARδ.
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Compound 4 alleviated hepatic steatosis, inflammation, and fibrosis in the NASH model.
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This study provided promising lead compound to explore better dual PPARα/δ agonists.

Abstract

Many peroxisome proliferator-activated receptors (PPARs) agonists have been developed for the treatment of metabolic disorders, while several PPARs agonists were discontinued in clinical trials because of PPARγ related side effects. In order to increase the selectivity against PPARγ, we performed a structure-activity relationship study based on PPARα/γ/δ agonist MHY2013. These efforts eventually led to the identification of compound 4, a dual PPARα/δ agonist with considerable potencies on PPARα/δ and high selectivity against PPARγ. In the Western Diet and CCl₄-induced non-alcoholic steatohepatitis model, compound 4 alleviates the hepatic steatosis, inflammation, and fibrosis. These results indicated that dual PPARα/δ agonist 4 might be a promising lead compound for further investigations.

Graphical abstract

Aiming to reduce the risk of PPARγ related side effect, we performed a SAR study based on MHY2013, and resulted in the discovery of dual PPARα/δ agonist 4.

Introduction

Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases, which includes different course of the disease, from hepatic steatosis to non-alcoholic steatohepatitis (NASH) followed by fibrosis [1], [2]. Although various factors including obesity, insulin resistance and inflammation have been attributed to the development of NAFLD, the exact pathogenesis is still unclear [3], [4]. To date, there are no approved drugs for NAFLD [5], [6].

The peroxisome proliferator-activated receptors (PPARs), including PPARα/δ/γ, have an important role in energy metabolism [7], [8], [9]. PPARα is primarily expressed in the liver and modulates plasma lipid levels, fatty acid β-oxidation and transport [10], [11], [12]. PPARδ is primarily expressed in muscle tissue, which modulates fatty acid transport and β-oxidation [13], [14]. Moreover, the activation of PPARδ improves plasma lipid levels and insulin sensitivity, and provides anti-inflammatory effects [15], [16], [17]. PPARγ is primarily expressed in adipocytes, which increases the storage of fatty acids and improves insulin resistance [18]. At present, many PPARs agonists (Fig. 1) have been developed for the treatment of dyslipidemia, NAFLD and diabetes [19], [20], [21]. In our previous study, we have also discovered several PPARδ agonists with a therapeutic effect on glucose and lipid metabolism [22], [23], [24]. Although the field is promising, several PPARs agonists were discontinued in clinical trials because of PPARγ related side effects such as weight gain, fluid retention, and cardiovascular risk [25], [26]. As a potent PPARα/γ/δ agonist, MHY2013 reduces insulin resistance, plasma lipid level and hepatic steatosis [27]. In order to decrease the risk of PPARγ related side effects, a lot of research has been done to obtain dual PPARα/δ agonist. Herein, we describe the structure-activity relationship study based on MHY2013 to further increase selectivity against PPARγ (Fig. 2).

Section snippets

Chemistry

The designed compounds 1–12 were synthesized as shown in Scheme 1. Treatment of commercially available B with phenol A using Williamson ether synthesis provided intermediate C, which was converted into benzimidazole with good yields [28], followed by hydrolysis provided the target compounds 1–12.

Structure-activity relationship study

In vitro activities of target compounds on PPARα/γ/δ were evaluated by using cell-based assays. As shown in Table 1, replacing benzothiazole of MHY2013 with benzimidazole provided compound 1 with

Conclusion

In order to decrease the risk of PPARγ related side effects, we performed a structure-activity relationship study based on PPARα/γ/δ agonist MHY2013. All of these efforts resulted in the discovery of dual PPARα/δ agonist 4, which revealed the best agonistic activity on PPARα/δ and high selectivity against PPARγ in our researches. Further modeling studies illuminated that compound 4 fitted very well with the binding pocket of PPARα and PPARδ, and formed multiple interactions with key residues

General chemistry

All starting materials, reagents, and solvents were obtained from commercial sources. Purifications of chromatography were performed by silica gel and detected by thin layer chromatography using UV light at 254 and 365 nm. Melting points were measured on RY-1 melting-point apparatus. NMR spectra were recorded on a Bruker ACF-300Q instrument (300 MHz for ¹H NMR and 75 MHz for ¹³C NMR spectra), chemical shifts are expressed as values (ppm) relative to tetramethylsilane as internal standard, and

Declaration of Competing Interest

The authors declare no competing financial interest.

Acknowledgments

This study was supported by the Natural Science Foundation of Guangdong Province, China (Grant 2018A030313445), the Guangdong Basic and Applied Basic Research Foundation, China (Grant 2019A1515011036), the Innovative strong school project of Guangdong Pharmaceutical University, China (Grant 2018KTSCX111), Guangdong Province Medical Science and Technology Research Fund, China (Grant B2018053), and Research Projects of the Chinese Medicine Council of Guangdong Province, China (Grant 20191199 and

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View full text

Discovery of novel dual PPARα/δ agonists based on benzimidazole scaffold for the treatment of non-alcoholic fatty liver disease

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Structure-activity relationship study

Conclusion

General chemistry

Declaration of Competing Interest

Acknowledgments

Gastroenterology

Metabolism

J. Hepatol.

Biochimie

Cell

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Chem.

Trends Endocrin. Met.

Tetrahedron

Bioorg. Med. Chem.

Biomed. Pharmacother.

J. Hepatol.

Nonalcoholic fatty liver disease: a systematic review

JAMA

Pathogenesis of NASH: the impact of multiple pathways

Curr. Hepatol. Rep.