INHIBITORS OF ACYL-COA CHOLESTEROL ACYLTRANSFERASE .5. IDENTIFICATION AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF NOVEL BETA-KETOAMIDES AS HYPOCHOLESTEROLEMIC AGENTS

被引：30

作者：

AUGELLISZAFRAN, CE ^{[1
]}

BLANKLEY, CJ ^{[1
]}

ROTH, BD ^{[1
]}

TRIVEDI, BK ^{[1
]}

BOUSLEY, RF ^{[1
]}

ESSENBURG, AD ^{[1
]}

HAMELEHLE, KL ^{[1
]}

KRAUSE, BR ^{[1
]}

STANFIELD, RL ^{[1
]}

机构：

[1] PARKE DAVIS PHARMACEUT RES,DEPT PHARMACOL,ANN ARBOR,MI 48105

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1993年 / 36卷 / 20期

关键词：

D O I：

10.1021/jm00072a014

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A study of structure-activity relationships of substituted beta-ketoamide ACAT inhibitors I and II was performed. The results of this study suggest that whereas the beta-keto group was tolerated with no loss in activity, beta-hydroxy and oxime moieties led to significantly reduced activity in vitro and in vivo. The most potent inhibitor from the acyclic series (I) (11, IC50 = 0.006 muM) contained a C-13 alkyl chain. This compound reduced plasma total cholesterol by 38% and 66% at 3 and 30 mg/kg, respectively, in cholesterol-fed rats. Dimethylation alpha to the anilide core(5) and subsequent N-methylation of the amide NH (6) decreased in vitro potency significantly. It was also found that high potency was retained with inhibitors which incorporated the carbonyl into a lactam ring (II).

引用

页码：2943 / 2949

页数：7

共 37 条

[1] POTENTIAL ANTI-ATHEROSCLEROTIC AGENTS .3. SUBSTITUTED BENZOIC AND NON BENZOIC-ACID ANALOGS OF CETABEN [J].

ALBRIGHT, JD ;

DEVRIES, VG ;

DU, MT ;

LARGIS, EE ;

MINER, TG ;

REICH, MF ;

SHEPHERD, RG .

JOURNAL OF MEDICINAL CHEMISTRY, 1983, 26 (10) :1393-1411

[2] POTENTIAL ANTI-ATHEROSCLEROTIC AGENTS .2. (ARALKYLAMINO)BENZOIC AND (ALKYLAMINO)BENZOIC ACID ANALOGS OF CETABEN [J].

ALBRIGHT, JD ;

DEVRIES, VG ;

LARGIS, EE ;

MINER, TG ;

REICH, MF ;

SCHAFFER, SA ;

SHEPHERD, RG ;

UPESLACIS, J .

JOURNAL OF MEDICINAL CHEMISTRY, 1983, 26 (10) :1378-1393

[3]

AUGELLISZAFRAN CE, 1991, 202ND NAT M NEW YORK

[4] ON THE MECHANISM BY WHICH AN ACAT INHIBITOR (CL-277,082) INFLUENCES PLASMA-LIPOPROTEINS IN THE RAT [J].

BALASUBRAMANIAM, S ;

SIMONS, LA ;

CHANG, S ;

ROACH, PD ;

NESTEL, PJ .

ATHEROSCLEROSIS, 1990, 82 (1-2) :1-5

[5] COMPARISON OF CI-976, AN ACAT INHIBITOR, AND SELECTED LIPID-LOWERING AGENTS FOR ANTIATHEROSCLEROTIC ACTIVITY IN ILIAC FEMORAL AND THORACIC AORTIC LESIONS - A BIOCHEMICAL, MORPHOLOGICAL, AND MORPHOMETRIC EVALUATION [J].

BOCAN, TMA ;

MUELLER, SB ;

UHLENDORF, PD ;

NEWTON, RS ;

KRAUSE, BR .

ARTERIOSCLEROSIS AND THROMBOSIS, 1991, 11 (06) :1830-1843

[6] POTENTIAL ANTI-ATHEROSCLEROTIC AGENTS .4. [(FUNCTIONALIZED-ALKYL)AMINO]BENZOIC ACID ANALOGS OF CETABEN [J].

DEVRIES, VG ;

LARGIS, EE ;

MINER, TG ;

SHEPHERD, RG ;

UPESLACIS, J .

JOURNAL OF MEDICINAL CHEMISTRY, 1983, 26 (10) :1411-1421

[7] POTENTIAL ANTIATHEROSCLEROTIC AGENTS .5. AN ACYL-COA - CHOLESTEROL O-ACYLTRANSFERASE INHIBITOR WITH HYPOCHOLESTEROLEMIC ACTIVITY [J].

DEVRIES, VG ;

SCHAFFER, SA ;

LARGIS, EE ;

DUTIA, MD ;

WANG, CH ;

BLOOM, JD ;

KATOCS, AS .

JOURNAL OF MEDICINAL CHEMISTRY, 1986, 29 (07) :1131-1133

[8] POTENTIAL ANTIATHEROSCLEROTIC AGENTS .6. HYPOCHOLESTEROLEMIC TRISUBSTITUTED UREA ANALOGS [J].

DEVRIES, VG ;

BLOOM, JD ;

DUTIA, MD ;

KATOCS, AS ;

LARGIS, EE .

JOURNAL OF MEDICINAL CHEMISTRY, 1989, 32 (10) :2318-2325

[9]

FIELD FJ, 1991, LIPIDS, V26, P1

[10] ANTIATHEROSCLEROTIC AGENTS - A STRUCTURALLY NOVEL BIVALENT INHIBITOR OF ACYLCOA-CHOLESTEROL O-ACYLTRANSFERASE WITH SYSTEMIC ACTIVITY [J].

GAMMILL, RB ;

BELL, FP ;

BELL, LT ;

BISAHA, SN ;

WILSON, GJ .

JOURNAL OF MEDICINAL CHEMISTRY, 1990, 33 (10) :2685-2686

← 1 2 3 4 →