In vivo Efficacy of Pyripyropene Derivatives in Atherogenic Mouse Models
Hiroshi Tomoda
Graduate School of Pharmaceutical Sciences, Kitasato University, Japan
Abstract:
Pyripyropene A (PPPA) produced by Aspergillus fumigatus FO-1289 is the first compound that strongly and selectively inhibits acyl-CoA:cholesterol acyltransferase 2 isozyme (ACAT2, IC50:>80 µM for ACAT1 vs. 70 nM for ACAT2). Firstly, in vivo efficacy of PPPA was investigated; when PPPA (10, 50, 100 mg/kg/day) was orally administered to apolipoprotein E knockout (ApoE-l-) mice for 12 weeks, plasma cholesterol levels as well as levels of very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) were lowered during the experiments, and the atherogenic lesion areas in the aortas and hearts dose-dependently reduced. Thus, we demonstrated PPPA is orally active in atherogenic mouse models. Secondly, PPPA derivatives were semisynthetically prepared. Among them, some acyl derivatives were found to exhibit more potent ACAT2 inhibitory activity and higher ACAT2 selectivity than PPPA. Thirdly, in vivo efficacy of the most active derivative 1 was similarly investigated in ApoE-l- mice. We demonstrated that 1 was more potent in vivo than PPPA, lowering plasma cholesterol levels and atherogenic lesion areas in the aortas and hearts. During the in vivo experiments, PPPA and the derivatives showed no toxic effects on mice. Thus, PPPA derivatives are expected to be potential as a new type of antiatherosclerotic agent.
