Molecular modelling, synthesis, and biological evaluations of a 3,5-disubstituted isoxazole fatty acid analogue as a PPARα-selective agonist

Henriette Arnesen,Nadia Nabil Haj-Yasein,Jørn E Tungen,Helen Soedling,Jason Matthews,Steinar M Paulsen,Hilde I Nebb,Ingebrigt Sylte,Trond Vidar Hansen,Thomas Sæther

doi:10.1016/j.bmc.2019.07.032

Henriette Arnesen, Nadia Nabil Haj-Yasein + Show 8 more

Open Access

https://doi.org/10.1016/j.bmc.2019.07.032

Copy DOI

Abstract

The peroxisome proliferator activated receptors (PPARs) are important drug targets in treatment of metabolic and inflammatory disorders. Fibrates, acting as PPARα agonists, have been widely used lipid-lowering agents for decades. However, the currently available PPARα targeting agents show low subtype-specificity and consequently a search for more potent agonists have emerged. In this study, previously isolated oxohexadecenoic acids from the marine algae Chaetoceros karianus were used to design a PPARα-specific analogue. Herein we report the design, synthesis, molecular modelling studies and biological evaluations of the novel 3,5-disubstituted isoxazole analogue 6-(5-heptyl-1,2-oxazol-3-yl)hexanoic acid (1), named ADAM. ADAM shows a clear receptor preference and significant dose-dependent activation of PPARα (EC50 = 47 µM) through its ligand-binding domain (LBD). Moreover, ADAM induces expression of important PPARα target genes, such as CPT1A, in the Huh7 cell line and primary mouse hepatocytes. In addition, ADAM exhibits a moderate ability to regulate PPARγ target genes and drive adipogenesis. Molecular modelling studies indicated that ADAM docks its carboxyl group into opposite ends of the PPARα and -γ LBD. ADAM interacts with the receptor-activating polar network of amino acids (Tyr501, His447 and Ser317) in PPARα, but not in PPARγ LBD. This may explain the lack of PPARγ agonism, and argues for a PPARα-dependent adipogenic function. Such compounds are of interest towards developing new lipid-lowering remedies.

Highlights

The peroxisome proliferator-activated receptors (PPARs) are ligandactivated nuclear receptors (NRs) with crucial roles in regulation of genes involved in a wide range of physiological processes
In response to ligand binding, the PPARs heterodimerize with retinoid X receptor (RXR) and act on specific PPAR response elements (PPREs) in chromatin
PPARγ is the PPAR subtype predominantly expressed in white adipocytes, the effects observed upon ADAM and Pirinixic acid treatment in this study indicates a function for PPARα in these cells

Summary

Introduction

The peroxisome proliferator-activated receptors (PPARs) are ligandactivated nuclear receptors (NRs) with crucial roles in regulation of genes involved in a wide range of physiological processes. The PPARs respond to endogenous ligands, such as metabolites of fatty acids, or synthetic compounds.[1,2,3] In response to ligand binding, the PPARs heterodimerize with retinoid X receptor (RXR) and act on specific PPAR response elements (PPREs) in chromatin. Ligand binding initiates conformational changes in the LBD that facilitates dissociation or recruitment of transcriptional co-regulators, mainly carried out by the liganddependent activation function 2 (AF2). The PPARs are well known for their control of genes involved in lipid and glucose metabolism. The PPARs are shown to encompass important roles in mediating biological effects related to inflammation and vascular function.[6,7,8]

Methods

Results

Conclusion