Synthesis and SAR study of corosolic acid derivatives

Corosolic acid is a naturally occurring pentacyclic triterpene acid which has attracted much attention due to its hypoglycemic activity.1 Recently, the Japanese researchersprovedfor thefirsttimethat1exhibitedaglucose-lowering effect on postchallenge plasma glucose levelsinhumans.2 Themechanismofhypoglycemicactionof 1 is not clear, nevertheless, according to the reported results of mechanic studies, it is likely that 1 might exert its glucose-lowing effect through multiple targets.

We have previously reported that 1 and related pentacyclic triterpenes are natural inhibitors of glycogen phosphorylase (GP), and they might reduce blood glucose, at least in part, through inhibiting excessive hepatic glycogenolysis.3c GP is the enzyme responsible for glycogen breakdown to produce glucose and related metabolites for energy supply. Recently, new insight into this enzyme has stimulated research interest in identifying safe and effective GP inhibitors as therapeutic agents for treatment of diabetes.4 Several structural classes of GP inhibitors have been developed, and at least six binding sites have been identified in GP.5 Although there is still a debate about whether GP could be an ideal drug target for diabetes, in our point of view, the key issue is about how to find PROPER small molecules to PROPERLY


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