INHIBITORS OF CHOLESTEROL-BIOSYNTHESIS .3. TETRAHYDRO-4-HYDROXY-6-[2-(1H-PYRROL-1-YL)ETHYL]-2H-PYRAN-2-ONE INHIBITORS OF HMG-COA REDUCTASE .2. EFFECTS OF INTRODUCING SUBSTITUENTS AT POSITIONS 3 AND 4 OF THE PYRROLE NUCLEUS

被引：143

作者：

ROTH, BD ^{[1
]}

BLANKLEY, CJ ^{[1
]}

CHUCHOLOWSKI, AW ^{[1
]}

FERGUSON, E ^{[1
]}

HOEFLE, ML ^{[1
]}

ORTWINE, DF ^{[1
]}

NEWTON, RS ^{[1
]}

SEKERKE, CS ^{[1
]}

SLISKOVIC, DR ^{[1
]}

STRATTON, CD ^{[1
]}

WILSON, MW ^{[1
]}

机构：

[1] WARNER LAMBERT PARKE DAVIS, DIV PHARMACEUT RES, DEPT PHARMACOL, ANN ARBOR, MI 48105 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1991年 / 34卷 / 01期

关键词：

D O I：

10.1021/jm00105a056

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of trans-tetrahydro-4-hydroxy-6-[2-(2,3,4,5-substituted-1H-pyrrol-1-yl)ethyl]-2H-pyran-2-ones and their dihydroxy acids were prepared and tested for their ability to inhibit the enzyme HMG-CoA reductase in vitro. Inhibitory potency was found to increase substantially when substituents were introduced into positions three and four of the pyrrole ring. A systematic exploration of structure-activity relationships at these two positions led to the identification of a compound ((+)-33, (+)-(4R)-trans-2-(4-fluorophenyl)-5-(1-methylethyl)-N,3-diphenyl-1-[(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-4-carboxamide) with five times the inhibitory potency of the fungal metabolite compactin.

引用

页码：357 / 366

页数：10

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