2. Academic Validation
  3. Design, synthesis, and biological evaluation of first-in-class FABP1 inhibitors for the treatment of NASH

Design, synthesis, and biological evaluation of first-in-class FABP1 inhibitors for the treatment of NASH

  • Eur J Med Chem. 2024 Apr 15:270:116358. doi: 10.1016/j.ejmech.2024.116358.
Ya Chen 1,  Mingyang Yu 2,  Lianru Chen 1,  Jianming Mao 1,  Wenxin Wang 1,  Zhongcheng Yang 1,  Zhijun Cao 2,  Yuxia Liu 2,  Min Wei 3,  Luyong Zhang 4,  Zheng Li 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
  • 2 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
  • 3 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China. Electronic address: min.wei@gdpu.edu.cn.
  • 4 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China. Electronic address: lyzhang@cpu.edu.cn.
  • 5 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou, 510006, PR China. Electronic address: lizhengdrug@gdpu.edu.cn.
PMID: 38574638 DOI: 10.1016/j.ejmech.2024.116358
Abstract

The fatty acid-binding protein 1 (FABP1) is a fatty acid transporter protein that is considered as an emerging target for metabolic diseases. Despite forceful evidence that the inhibition of FABP1 is essential for ameliorating NASH, pharmacological control and validation of FABP1 are hindered by a lack of relevant inhibitors as pharmacological tool. Therefore, the development of effective FABP1 inhibitors is a current focus of research. Herein, we firstly reported the comprehensive structure-activity relationship (SAR) study of novel FABP1 inhibitors derived from high throughput screening of our in-house library, which resulting in the identification of the optimal compound 44 (IC50 = 4.46 ± 0.54 μM). Molecular docking studies revealed that 44 forms stable hydrogen bonds with Amino acids around the active pocket of FABP1. Moreover, 44 alleviated the typical histological features of fatty liver in NASH mice, including steatosis, lobular inflammation, ballooning and fibrosis. Additionally, 44 has been demonstrated to have lipid metabolism regulating, anti-oxidative stress and hepatoprotective properties. This study might be provided a promising insight into the field of NASH and inspiration for the development of FABP1 inhibitors.

Keywords

FABP1; Fibrosis; Inflammation; Lipid metabolism; NAFLD; Oxidative stress.

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