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. [ABSTRACT FROM AUTHOR]