The induction of activating transcription factor 3 (ATF3) was identified as a promising therapeutic mechanism to overcome metabolic syndrome. Hence, a structure-activity relationship campaign on the chiral lead (1b) was conducted with a scaffold-hopping approach, whereby achiral 7-methoxy-3-methyl-1H-chromeno[4,3-c]pyrazol-4-one (16c) was recognized as a potential ATF3 inducer with a lipid-lowering feature in a pre-differentiated 3T3-L1 cell model. Also, in a high-fat diet scenario, mice subjected to 16c demonstrated robust weight loss with shrinkage of the white adipose mass and fewer hypertrophic adipocytes, accompanied by a preferable glycemic profile compared to 1b. Additionally, the biochemical analysis revealed that 16c further ameliorated the liver function and improved the plasma triglyceride profile that were absent from mice treated with 1b. Taken together, 16c shows promise as an ATF3 stimulant for further development to alleviate metabolic syndrome.

激活转录因子 3 (ATF3) 的诱导被确定为克服代谢综合征的有前途的治疗机制。因此，采用脚手架跳跃方法对手性先导化合物 ( 1b ) 进行了构效关系研究，其中非手性 7-methoxy-3-methyl-1 H -chromeno[4,3 - c ]pyrazol-4-one ( 16c ) 被认为是一种潜在的 ATF3 诱导剂，在预分化的 3T3-L1 细胞模型中具有降脂功能。此外，在高脂肪饮食情况下，接受16c的小鼠体重明显减轻，白色脂肪体积缩小，肥大脂肪细胞减少，同时血糖状况优于1b. 此外，生化分析显示16c进一步改善了肝功能并改善了血浆甘油三酯谱，而这些在1b处理的小鼠中是不存在的。综上所述，16c有望作为 ATF3 兴奋剂进一步开发以减轻代谢综合征。