DISCOVERY OF MK-0476, A POTENT AND ORALLY-ACTIVE LEUKOTRIENE D-4 RECEPTOR ANTAGONIST DEVOID OF PEROXISOMAL ENZYME-INDUCTION

被引：88

作者：

LABELLE, M ^{[1
]}

BELLEY, M ^{[1
]}

GAREAU, Y ^{[1
]}

GAUTHIER, JY ^{[1
]}

GUAY, D ^{[1
]}

GORDON, R ^{[1
]}

GROSSMAN, SG ^{[1
]}

JONES, TR ^{[1
]}

LEBLANC, Y ^{[1
]}

MCAULIFFE, M ^{[1
]}

MCFARLANE, C ^{[1
]}

MASSON, P ^{[1
]}

METTERS, KM ^{[1
]}

OUIMET, N ^{[1
]}

PATRICK, DH ^{[1
]}

PIECHUTA, H ^{[1
]}

ROCHETTE, C ^{[1
]}

SAWYER, N ^{[1
]}

XIANG, YB ^{[1
]}

PICKETT, CB ^{[1
]}

FORDHUTCHINSON, AW ^{[1
]}

ZAMBONI, RJ ^{[1
]}

YOUNG, RN ^{[1
]}

机构：

[1] MERCK & CO INC,DEPT SAFETY ASSESSMENT,W POINT,PA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 1995年 / 5卷 / 03期

关键词：

D O I：

10.1016/0960-894X(95)00023-M

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structure-activity studies leading to the discovery of 1 (MK-0476) are described. The initial compound of this series, 2, was a potent leukotriene D-4 (LTD(4)) antagonist, but was also a peroxisomal enzyme inducer in the mouse. Structure-activity relationships around the thioether chain were explored to remove this undesirable feature. It was found that alkyl substituents in the beta position relative to the carboxylic acid reduce the potency as a peroxisomal enzyme inducer while preserving the LTD(4) antagonistic properties. Dialkyl substitution essentially eliminates the enzyme induction. The optimal styryl quinoline 1 exhibited high in vitro potency and in vivo activity on oral dosing without significant liver enzyme induction in the mouse.

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页码：283 / 288

页数：6

相关论文

共 27 条

[1] PEROXISOME PROLIFERATION AND MODULATION OF RAT-LIVER CARCINOGENESIS BY 2,4-DICHLOROPHENOXYACETIC ACID, 2,4,5-TRICHLOROPHENOXYACETIC ACID, PERFLUOROOCTANOIC ACID AND NAFENOPIN [J].

ABDELLATIF, AG ;

PREAT, V ;

VAMECQ, J ;

NILSSON, R ;

ROBERFROID, M .

CARCINOGENESIS, 1990, 11 (11) :1899-1902

[2] EFFECTS OF CHRONIC TREATMENT WITH THE LEUKOTRIENE D4-ANTAGONIST COMPOUND-LY171883 ON B6C3F1 MICE [J].

BENDELE, AM ;

HOOVER, DM ;

VANLIER, RBL ;

FOXWORTHY, PS ;

EACHO, PI .

FUNDAMENTAL AND APPLIED TOXICOLOGY, 1990, 15 (04) :676-682

[3] ALKYLTHIOACETIC ACID (3-THIA FATTY-ACIDS) - A NEW GROUP OF NON-BETA-OXIDIZABLE, PEROXISOME-INDUCING FATTY-ACID ANALOGS .1. A STUDY ON THE STRUCTURAL REQUIREMENTS FOR PROLIFERATION OF PEROXISOMES AND MITOCHONDRIA IN RAT-LIVER [J].

BERGE, RK ;

AARSLAND, A ;

KRYVI, H ;

BREMER, J ;

AARSAETHER, N .

BIOCHIMICA ET BIOPHYSICA ACTA, 1989, 1004 (03) :345-356

[4] ALKYLTHIO ACETIC-ACIDS (3-THIA FATTY-ACIDS) - A NEW GROUP OF NON-BETA-OXIDIZABLE PEROXISOME-INDUCING FATTY-ACID ANALOGS .2. DOSE-RESPONSE STUDIES ON HEPATIC PEROXISOMAL CHANGES AND MITOCHONDRIAL CHANGES AND LONG-CHAIN FATTY-ACID METABOLIZING ENZYMES IN RATS [J].

BERGE, RK ;

AARSLAND, A ;

KRYVI, H ;

BREMER, J ;

AARSAETHER, N .

BIOCHEMICAL PHARMACOLOGY, 1989, 38 (22) :3969-3979

[5]

BOIE Y, 1993, J BIOL CHEM, V268, P5530

[6]

BOTTO A, 1994, AM J RESP CRIT CARE, V149, pA465

[7] HIGHLY ENANTIOSELECTIVE BORANE REDUCTION OF KETONES CATALYZED BY CHIRAL OXAZABOROLIDINES - MECHANISM AND SYNTHETIC IMPLICATIONS [J].

COREY, EJ ;

BAKSHI, RK ;

SHIBATA, S .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1987, 109 (18) :5551-5553

[8] INDUCTION OF PEROXISOMAL BETA-OXIDATION IN THE RAT-LIVER INVIVO AND INVITRO BY TETRAZOLE-SUBSTITUTED ACETOPHENONES - STRUCTURE ACTIVITY RELATIONSHIPS [J].

EACHO, PI ;

FOXWORTHY, PS ;

DILLARD, RD ;

WHITESITT, CA ;

HERRON, DK ;

MARSHALL, WS .

TOXICOLOGY AND APPLIED PHARMACOLOGY, 1989, 100 (01) :177-184

[9] THE STEREOSELECTIVE ALPHA-ALKYLATION OF CHIRAL BETA-HYDROXY ESTERS AND SOME APPLICATIONS THEREOF [J].

FRATER, G ;

MULLER, U ;

GUNTHER, W .

TETRAHEDRON, 1984, 40 (08) :1269-1277

[10] CHARACTERIZATION OF THE LEUKOTRIENE D4 RECEPTOR IN DIMETHYLSULFOXIDE-DIFFERENTIATED-U937 CELLS - COMPARISON WITH THE LEUKOTRIENE-D4 RECEPTOR IN HUMAN LUNG AND GUINEA-PIG LUNG [J].

FREY, EA ;

NICHOLSON, DW ;

METTERS, KM .

EUROPEAN JOURNAL OF PHARMACOLOGY-MOLECULAR PHARMACOLOGY SECTION, 1993, 244 (03) :239-250