title: Selectivity of pyripyropene derivatives in inhibition toward acyl-CoA:cholesterol acyltransferase 2 isozyme.
abstract: Selectivity of 96 semisynthetic derivatives prepared from fungal pyripyropene A, originally isolated as a potent inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), toward ACAT1 and ACAT2 isozymes was investigated in the cell-based assay using ACAT1- and ACAT2-expressing CHO cells. Eighteen derivatives including PR-71 (7-O-isocaproyl derivative) showed much more potent ACAT2 inhibition (IC50: 6.0 to 62 nM) than pyripyropene A (IC50: 70 nM). Among them, however, natural pyripyropene A showed the highest selectivity toward ACAT2 with a selectivity index (SI) of >1000, followed by PR-71 (SI, 667).
authors.affiliation: School of Pharmacy, Kitasato University, Tokyo, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Ohshiro
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ohte
authors.forename: Daisuke
authors.initials: D
authors.lastname: Matsuda
authors.forename: Masaki
authors.initials: M
authors.lastname: Ohtawa
authors.forename: Tohru
authors.initials: T
authors.lastname: Nagamitsu
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sunazuka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Harigaya
authors.forename: Lawrence L
authors.initials: LL
authors.lastname: Rudel
authors.forename: Satoshi
authors.initials: S
authors.lastname: Omura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tomoda
mesh_terms: D000818:Animals; D016466:CHO Cells; D002788:Cholesterol Esters / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007527:Isoenzymes; D019301:Oleic Acid / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D012717:Sesquiterpenes / Q000494:pharmacology*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity; D000097587:Sterol O-Acyltransferase 2
chemical_list: D002788:Cholesterol Esters; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D019301:Oleic Acid; D011725:Pyridines; D012717:Sesquiterpenes; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; C082792:pyripyropene A; C493492:sterol O-acyltransferase 1