Design, synthesis, and biological evaluation of novel FFA1 partial agonists bearing oxime ether scaffold**

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.