Discovery of PPARγ and glucocorticoid receptor dual agonists to promote the adiponectin and leptin biosynthesis in human bone marrow mesenchymal stem cells

Adiponectin and Leptin are major adipocytokines that control crosstalk between adipose tissue and other organ systems. Hypoadiponectinemia and hypoleptinemia are associated with human metabolic diseases. Compounds with adipocytokine biosynthesis-stimulating activities could be developed as therapeutics against diverse metabolic conditions. In phenotypic screening with human bone marrow mesenchymal stem cells (hBM-MSCs), (E)-4-hydroxy-3-(3-(4-hydroxy-3-methoxyphenyl)acryloyl)-6-methyl-2H-pyran-2-one (1) was identified to increase Adiponectin biosynthesis during adipogenesis and simultaneously to stimulate Leptin production. Using the compound 1 structure, the structure-activity relationship study was performed to discover more potent compounds stimulating both Adiponectin and Leptin production. (E)-3-(3-(2-fluoropyridin-4-yl)acryloyl)-4-hydroxy-6-methyl-2H-pyran-2-one (11) exhibited the most potent Adiponectin (EC₅₀, 2.87 μM) and Leptin (EC₅₀, 2.82 μM) biosynthesis-stimulating activities in hBM-MSCs. In a target identification study, compound 11 was characterized as a dual modulator binding to both Peroxisome Proliferator-activated Receptor (PPAR) γ and Glucocorticoid Receptor (GR). This study provides a novel pharmacophore for PPARγ/GR dual modulators with therapeutic potential against human metabolic diseases.

Adiponectin; Human bone marrow mesenchymal stem cells; Leptin; PPARγ and glucocorticoid receptor dual modulator; Target identification.