CHEMICAL MODIFICATION AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF PYRIPYROPENES .1. MODIFICATION AT THE 4 HYDROXYL-GROUPS

Four hydroxyl groups of pyripyropenes have been modified and evaluated for their ability to inhibit microsomal acyl-CoA:cholesterol acyltran sferase (ACAT) activity in vitro and to lower cholesterol absorption i n vivo in a cholesterol-fed hamster. 7-O-n-Valeryl derivative (8c) imp roved the in vitro ACAT inhibitory activity (IC50=13 nM) about 7 times better than pyripyropene A. Introduction of methanesulfonyl group at 11-hydroxyl group (17a) increased both in vitro activity (IC50=19 nM) and in vivo efficacy (ED(50)=10 mg/kg).