期刊
CHEMISTRYSELECT
卷 7, 期 2, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/slct.202104199
关键词
AMG-837; Diabetes; Drug design; FFA1; Lipophilicity
资金
- Key Field R&D Plan Project of Guangdong province [2019B020201002]
- Guangdong Basic and Applied Basic Research Foundation [2019A1515011036]
- Basic Research Program of Yunnan Province (Kunming Medical University Joint Special Project) [202101AY070001-276]
- Yunnan Clinical Medical Center for Endocrinology and Metabolic Diseases [zx2019-02-02, nfm202107]
- Open Project of Guangxi Key Laboratory of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention [GXXNXG202101]
- National Key Clinical Specialty Construction Project (Clinical Pharmacy)
- High Level Clinical Key Specialty (Clinical Pharmacy) in Guangdong Province
This study successfully developed a partial agonist of the free fatty acid receptor 1 (FFA1) with reduced lipophilicity, which showed good activity in lowering blood glucose.
The free fatty acid receptor 1 (FFA1) is a promising anti-diabetic target, and many FFA1 agonists including TAK-875 and AMG-837 are reached in clinical studies. However, the excessive lipophilicity of AMG-837 (ClogP=6.81) might be a potential downside attributed to the clinical failure of AMG-837. In this study, we introduced the oxime ether moiety to replace the middle benzene of AMG-837 to reduce the lipophilicity. After comprehensive structure-activity relationship study, the optimal compound 7 was identified as a partial agonist with appropriate lipophilicity (EC50=37.6 nM, Efficacy=71 %, ClogP=4.73). Moreover, compound 7 exhibited significantly glucose-lowering effects in a dose-dependent manner, and the glucose-lowering effect was equivalent to that of TAK-875 at the dose of 20 mg/kg. In conclusion, this study provided a new series partial agonists bearing oxime ether scaffold, which is worthy for further exploration based on its excellent pharmacological activity and physicochemical property.
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