Chemical modification and structure-activity relationships of pyripyropenes. 1. Modification at the four hydroxyl groups

Four hydroxyl groups of pyripyropenes have been modified and evaluated for their ability to inhibit microsomal acyl-CoA: cholesterol acyltransferase (ACAT) activity in vitro and to lower cholesterol absorption in vivo in a cholesterol-fed hamster. 7-O-n-Valeryl derivative (8c) improved 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 (ED₅₀ = 10 mg/kg).