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

  • Eur J Med Chem. 2023 Jan 5;245(Pt 1):114927. doi: 10.1016/j.ejmech.2022.114927.
Sungjin Ahn  1 ,  Myunghwan Ahn  2 ,  Suzie Park  2 ,  Seungchan An  1 ,  In Guk Park  1 ,  Seok Young Hwang  1 ,  Junpyo Gong  1 ,  Soyeon Oh  1 ,  Sun Hee Jin  1 ,  Hee Jin Kim  3 ,  Jae Hoon Cheong  4 ,  Youngjoo Byun  5 ,  Minsoo Noh  6
Affiliations
  • 1. College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul, 08826, Republic of Korea.
  • 2. College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong, 30019, Republic of Korea.
  • 3. Uimyung Research Institute for Neuroscience, Sahmyook University, 26-21 Kongreung-2-dong, Hwarangro-815, Nowon-gu, Seoul, 139-742, Republic of Korea.
  • 4. School of Pharmacy, Jeonbuk National University, Jeonju, 54896, Republic of Korea.
  • 5. College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong, 30019, Republic of Korea. Electronic address: [email protected].
  • 6. College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul, 08826, Republic of Korea. Electronic address: [email protected].
PMID: 36379105 DOI: 10.1016/j.ejmech.2022.114927
Abstract

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.

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