2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel highly selective non-carboxylic acid FABP1 inhibitors

Design, synthesis, and biological evaluation of novel highly selective non-carboxylic acid FABP1 inhibitors

  • Eur J Med Chem. 2024 Oct 5:276:116705. doi: 10.1016/j.ejmech.2024.116705.
Lianru Chen 1,  Bin Wang 1,  Hongming Li 2,  Jianming Mao 1,  Zhiling Liang 1,  Ya Chen 1,  Mingyang Yu 1,  Yuxia Liu 1,  Zibin Liao 1,  Yuanqian Yang 1,  Xiaojing Wu 1,  Huazheng Wang 1,  Yonghong Yang 1,  Ruojing Xiang 1,  Luyong Zhang 3,  Zheng Li 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
  • 2 Fujian Provincial Key Laboratory of Hepatic Drug Research, Ningde, 355300, PR China.
  • 3 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.
  • 4 School of Pharmacy, 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; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou, 510006, PR China. Electronic address: lizhengdrug@gdpu.edu.cn.
PMID: 39067439 DOI: 10.1016/j.ejmech.2024.116705
Abstract

Histologic spectrum studies in patients revealed fatty acid binding proteins 1 (FABP1) as a potential new target for the treatment of metabolic associated fatty liver disease. However, there is no FABP1 inhibitor has been reported except the first-in-class FABP1 inhibitor bearing acid moiety reported by our laboratory. Herein, we firstly report the structure-activity relationship of novel non-carboxylic acid FABP1 inhibitors, which resulted in the identification of the potent and selective FABP1 inhibitor 30. The IC50 value of compound 30 for subtype FABP4 in the same family was greater than 80 μM. Moreover, compound 30 significantly alleviated the hepatic steatosis in DIO mice, which is equivalent to that of clinical drug obeticholic acid. This study might be provided a promising probe for the development of FABP1 inhibitors and thus can help to further elucidate the pharmacology of FABP1.

Keywords

FABP1; Hepatic steatosis; Lipid metabolism; MASLD.

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