1. Academic Validation
  2. Exploration and biological evaluation of 7-methoxy-3-methyl-1H-chromeno[4,3-c]pyrazol-4-one as an activating transcription factor 3 inducer for managing metabolic syndrome

Exploration and biological evaluation of 7-methoxy-3-methyl-1H-chromeno[4,3-c]pyrazol-4-one as an activating transcription factor 3 inducer for managing metabolic syndrome

  • Eur J Med Chem. 2023 Jan 15:246:114951. doi: 10.1016/j.ejmech.2022.114951.
Yi-Han Chang 1 Heng Lin 2 Hsiao-Fen Li 2 Hsi-Hsien Chen 3 Hsin-Yi Hung 4
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan, ROC.
  • 2 Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan, ROC.
  • 3 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan, ROC; Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, 11031, Taiwan, ROC; TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei, 11031, Taiwan, ROC; Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan, ROC.
  • 4 School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan, ROC. Electronic address: [email protected].
Abstract

The induction of activating transcription factor 3 (ATF3) was identified as a promising therapeutic mechanism to overcome metabolic syndrome. Hence, a structure-activity relationship campaign on the chiral lead (1b) was conducted with a scaffold-hopping approach, whereby achiral 7-methoxy-3-methyl-1H-chromeno[4,3-c]pyrazol-4-one (16c) was recognized as a potential ATF3 inducer with a lipid-lowering feature in a pre-differentiated 3T3-L1 cell model. Also, in a high-fat diet scenario, mice subjected to 16c demonstrated robust weight loss with shrinkage of the white adipose mass and fewer hypertrophic adipocytes, accompanied by a preferable glycemic profile compared to 1b. Additionally, the biochemical analysis revealed that 16c further ameliorated the liver function and improved the plasma triglyceride profile that were absent from mice treated with 1b. Taken together, 16c shows promise as an ATF3 stimulant for further development to alleviate metabolic syndrome.

Keywords

Activating transcription factor 3; Metabolic syndrome; Scaffold-hopping; Structure-activity relationship.

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