2. Academic Validation
  3. Development of FABP4/5 inhibitors with potential therapeutic effect on type 2 Diabetes Mellitus

Development of FABP4/5 inhibitors with potential therapeutic effect on type 2 Diabetes Mellitus

  • Eur J Med Chem. 2021 Nov 15:224:113720. doi: 10.1016/j.ejmech.2021.113720.
Yu-Long He 1,  Meng-Ting Chen 2,  Ting Wang 3,  Ming-Ming Zhang 1,  Ying-Xia Li 4,  He-Yao Wang 5,  Ning Ding 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4 School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: [email protected].
  • 6 School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: [email protected].
PMID: 34332399 DOI: 10.1016/j.ejmech.2021.113720
Abstract

Fatty acid-binding protein 4 (FABP4) and fatty acid-binding protein 5 (FABP5) are promising therapeutic targets for the treatment of various metabolic diseases. However, the weak potency, low selectivity over FABP3, or poor pharmacokinetic profiles of currently reported dual FABP4/5 inhibitors impeded further research. Here, we described the characterization of a series of dual FABP4/5 inhibitors with improved metabolic stabilities and physicochemical properties based on our previous studies. Among the compounds, D9 and E1 exhibited good inhibitory activities against FABP4/5 and favorable selectivity over FABP3 in vitro. In cell-based assays, D9 and E1 exerted a decrease of FABP4 secretion, a strong anti-lipolytic effect in mature adipocytes, and suppression of MCP-1 expression in THP-1 macrophages. Moreover, D9 and E1 possessed good metabolic stabilities in mouse hepatic microsomes and acceptable pharmacokinetics profiles in ICR mice. Further in vivo experiments showed that D9 and E1 could potently decrease serum FABP4 levels and ameliorate glucose metabolism disorders in obese diabetic db/db mice. These results demonstrated that D9 and E1 could serve as lead compounds for the development of novel anti-diabetic drugs.

Keywords

Anti-diabetic activities; Anti-lipolytic and anti-inflammatory effects; Dual FABP4/5 inhibitors; Metabolic stability; Type 2 diabetes mellitus.

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