THE SQUALESTATINS - NOVEL INHIBITORS OF SQUALENE SYNTHASE - ENZYME-INHIBITORY ACTIVITIES AND IN-VIVO EVALUATION OF C1-MODIFIED ANALOGS

被引：20

作者：

PROCOPIOU, PA

BAILEY, EJ

BAMFORD, MJ

CRAVEN, AP

DYMOCK, BW

HOUSTON, JG

HUTSON, JL

KIRK, BE

MCCARTHY, AD

SAREEN, M

SCICINSKI, JJ

SHARRATT, PJ

SNOWDEN, MA

WATSON, NS

WILLIAMS, RJ

机构：

[1] GLAXO GRP RES LTD,DEPT BIOCHEM TARGETS,GREENFORD UB6 0HE,MIDDX,ENGLAND

[2] GLAXO GRP RES LTD,DEPT MOLEC SCI,GREENFORD UB6 0HE,MIDDX,ENGLAND

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1994年 / 37卷 / 20期

关键词：

D O I：

10.1021/jm00046a011

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Squalestatin analogues modified in the C1 side chain were prepared and evaluated for their ability to inhibit rat liver microsomal and Candida squalene synthase (SQS) in vitro. While maintaining the 4,6-dimethyloctenoate or 4,6-dimethyloctanoate ester groups at C6, a number of modifications to the C1 side chain were well tolerated. However, in the absence of the C6 ester group, similar modifications to the C1 side chain caused substantial loss of activity. Compounds were also evaluated for their ability to inhibit cholesterol biosynthesis in vivo in rats and to reduce serum cholesterol levels in marmosets. These studies revealed that compounds with similar SQS inhibitory activities can possess different in vivo durations of action and lipid-lowering abilities.

引用

页码：3274 / 3281

页数：8

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