Selectivity of Pyripyropene Derivatives in Inhibition toward Acyl-CoA:cholesterol Acyltransferase 2 Isozyme

被引：0
作者：
Taichi Ohshiro
Satoshi Ohte
Daisuke Matsuda
Masaki Ohtawa
Tohru Nagamitsu
Toshiaki Sunazuka
Yoshihiro Harigaya
Lawrence L Rudel
Satoshi Ōmura
Hiroshi Tomoda
机构：
[1] School of Pharmacy,
[2] Kitasato University,undefined
[3] School of Pharmacy,undefined
[4] Kitasato University,undefined
[5] Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences,undefined
[6] Kitasato University,undefined
[7] Atherosclerosis Research Program,undefined
[8] Wake Forest University School of Medicine,undefined
来源：
The Journal of Antibiotics | 2008年 / 61卷
关键词：
semisynthetic pyripyropene derivative; acyl-CoA:cholesterol acyltransferase (ACAT); ACAT isozyme; atherosclerosis;
D O I：
暂无
中图分类号：
学科分类号：
摘要：
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).
引用
收藏
页码：503 / 508
页数：5
相关论文
共 142 条
[1]  
Roth BD(1998)ACAT inhibitors: Evolution from cholesterol-absorption inhibitors to antiatherosclerotic agents Drug Disc Today 3 19-25
[2]  
Tardif JC(2004)Effects of the acyl coenzyme A:cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions Circulation 110 3372-3377
[3]  
Gregoire J(2006)Effect of ACAT inhibition on the progression of coronary atherosclerosis N Engl J Med 354 1253-1263
[4]  
L'Allier PL(2007)Potential therapeutics for obesity and atherosclerosis: inhibitors of neutral lipid metabolism from microorganisms Pharmacol Ther 115 375-389
[5]  
Anderson TJ(1993)Pyripyropenes highly potent inhibitors of acyl-CoA:cholesterol acyltransferase produced by J Antibiot 46 1168-1169
[6]  
Bertrand O(1994)Pyripyropenes, novel inhibitors of acyl-CoA:cholesterol acyltransferase produced by J Antibiot 47 148-153
[7]  
Reeves F(1994). I. Production, isolation, and biological properties J Antibiot 47 154-162
[8]  
Title LM(1995)Pyripyropenes, novel inhibitors of acyl-CoA:cholesterol acyltransferase produced by J Antibiot 48 749-750
[9]  
Alfonso F(1995). II. Structure elucidation of pyripyropenes A, B, C and D Bioog Med Chem Lett 5 2683-2688
[10]  
Schampaert E(1996)Structureactivity relationships of pyripyropenes, fungal acyl-CoA:cholesterol acyltransferase inhibitors J Antibiot 49 1133-1148
12345678910