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
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
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DOI：
10.1021/jm00105a056
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发表时间：
1991-01-01
影响因子：
7.3
通讯作者：
WILSON, MW
中科院分区：
文献类型：
--
作者：
ROTH, BD;BLANKLEY, CJ;WILSON, MW
制备了一系列反式-四氢-4-羟基-6-[2-（2，3，4，5-取代-1H-吡咯-1-基）乙基]-2H-吡喃-2-酮及其二羟基酸，并测试了它们体外抑制酶HMG-CoA还原酶的能力。当吡咯环的三位和四位引入取代基时，抑制效力被发现大大增加。对这两个位置的结构-活性关系的系统探索导致鉴定出化合物（（+）-33，（+）-（4 R）-反式-2-（4-氟苯基）-5-（1-甲基乙基）-N，3-二苯基-1-[（四氢-4-羟基-6-氧代-2H-吡喃-2-基）乙基]-1H-吡咯-4-甲酰胺），其抑制效力是真菌代谢物康伐菌素的5倍。
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.