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).
Obata
R
R
Research Center for Biological Function, Kitasato Institute, Kitasato University, Tokyo, Japan.
Sunazuka
T
T
Li
Z
Z
Tian
Z
Z
Harigaya
Y
Y
Tabata
N
N
Tomoda
H
H
Omura
S
S
D000818:Animals; D002784:Cholesterol / Q000493:pharmacokinetics; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D011753:Pyrones / Q000737:chemistry* / Q000494:pharmacology*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011725:Pyridines; D011753:Pyrones; D002784:Cholesterol; D002785:Sterol O-Acyltransferase