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

Autor: Henriette Arnesen, Helen Soedling, Jason Matthews, Thomas Sæther, Hilde I. Nebb, Ingebrigt Sylte, Nadia Nabil Haj-Yasein, Steinar M. Paulsen, Jørn Eivind Tungen, Trond Vidar Hansen
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Models
Molecular
Agonist
Peroxisome proliferator activated receptor
medicine.drug_class
Clinical Biochemistry
Pharmaceutical Science
Peroxisome proliferator-activated receptor
01 natural sciences
Biochemistry
chemistry.chemical_compound
Isoxazole
Drug Discovery
medicine
Microalgae
Humans
PPAR alpha
Oxohexadecenoic acid
Receptor
Molecular Biology
chemistry.chemical_classification
010405 organic chemistry
Chaetoceros karianus
Lipid-lowering
Fatty Acids
Organic Chemistry
Fatty acid
VDP::Medisinske Fag: 700::Basale medisinske
odontologiske og veterinærmedisinske fag: 710
Isoxazoles
VDP::Medical disciplines: 700::Basic medical
dental and veterinary science disciplines: 710
0104 chemical sciences
Amino acid
010404 medicinal & biomolecular chemistry
chemistry
Adipogenesis
Molecular Medicine
Function (biology)
Zdroj: Bioorganic & Medicinal Chemistry
ISSN: 4059-4068
0968-0896
Popis: 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 (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.
Databáze: OpenAIRE
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