Structure-Based Optimization and Biological Evaluation of Pancreatic Lipase Inhibitors as Novel Potential Antiobesity Agents

摘要

The unusual fused β-lactone vibralactone was isolated from cultures of the basidiomycete Boreostereum vibrans and has been shown to significantly inhibit pancreatic lipase. In this study, a structure-based lead optimization of vibralactone resulted in three series of 104 analogs, among which compound >C1 exhibited the most potent inhibition of pancreatic lipase, with an IC50 value of 14 nM. This activity is more than 3000-fold higher than that of vibralactone. The effect of compound >C1 on obesity was investigated using high-fat diet (HFD)-induced C57BL/6 J obese mice. Treatment with compound >C1 at a dose of 100 mg/kg significantly decreased HFD-induced obesity, primarily through the improvement of metabolic parameters, such as triglyceride levels.Electronic supplementary materialThe online version of this article (doi:10.1007/s13659-015-0062-6) contains supplementary material, which is available to authorized users.