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

• Published in: Bioorganic & Medicinal Chemistry
• Main Authors: Arnesen, Henriette, Haj-Yasein, Nadia N., Tungen, Jørn E., Soedling, Helen, Matthews, Jason, Paulsen, Steinar M., Nebb, Hilde I., Sylte, Ingebrigt, Hansen, Trond Vidar, Sæther, Thomas
• Format: Article in Journal/Newspaper
• Language: English
• Published: Elsevier 2019
• Subjects: VDP::Medical disciplines: 700::Basic medical; dental and veterinary science disciplines: 710; VDP::Medisinske Fag: 700::Basale medisinske; odontologiske og veterinærmedisinske fag: 710; Peroxisome proliferator activated receptor; Agonist; Oxohexadecenoic acid; Isoxazole; Lipid-lowering; Microalgae; Chaetoceros karianus; Arctic
• Online Access: https://hdl.handle.net/10037/16078; https://doi.org/10.1016/j.bmc.2019.07.032

Source at https://doi.org/10.1016/j.bmc.2019.07.032. 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 (EC 50 = 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.