A NOVEL SERIES OF SELECTIVE LEUKOTRIENE ANTAGONISTS - EXPLORATION AND OPTIMIZATION OF THE ACIDIC REGION IN 1,6-DISUBSTITUTED INDOLES AND INDAZOLES

被引：57

作者：

YEE, YK ^{[1
]}

BERNSTEIN, PR ^{[1
]}

ADAMS, EJ ^{[1
]}

BROWN, FJ ^{[1
]}

CRONK, LA ^{[1
]}

HEBBEL, KC ^{[1
]}

VACEK, EP ^{[1
]}

KRELL, RD ^{[1
]}

SNYDER, DW ^{[1
]}

机构：

[1] ICI PHARMACEUT GRP, DEPT PHARMACOL, WILMINGTON, DE 19897 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1990年 / 33卷 / 09期

关键词：

D O I：

10.1021/jm00171a018

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A systematic structure-activity exploration of the carboxylic acid region in a series of indole- or indazole-derived leukotriene antagonists 1 led to several discoveries. Use of the 3-methoxy-p-tolyl fragment (illustrated in acid 1) for connecting the indole and the acidic site provides the most potent carboxylic acids 1, tetrazoles 20, and aryl sulfonimides 21. The aryl sulfonimides are 5-500 times more potent (in vitro and/or in vivo) than the corresponding carboxylic acids 1. The o-tolyl sulfonimides such as 114 show greater oral potency than the phenyl sulfonimides at a given level of in vitro activity. Acidic keto sulfone derivatives 10 (Nu = CH(CO2CH3)SO2Ph) mimic the activity of the sulfonimides.

引用

页码：2437 / 2451

页数：15

共 40 条

[1] IONIZATION OF HYDROXAMIC ACIDS IN AQUEOUS-SOLUTIONS [J].

ABBASI, SA ;

AHMED, J .

BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, 1976, 49 (07) :2013-2014

[2]

AHARONY D, 1989, J PHARMACOL EXP THER, V248, P581

[3]

AHARONY D, 1987, J PHARMACOL EXP THER, V243, P921

[4]

AHARONY D, 1988, ANN NY ACAD SCI, V524, P162

[5]

[Anonymous], 1970, CHEM INDOLES

[6]

BERNSTEIN PR, 1987, SYNTHESIS-STUTTGART, P1133

[7]

BERNSTEIN PR, 1985, Patent No. 4499299

[8] Sulfuration of ethyl-benzoel aniline [J].

Blangey, L ;

Fierz-David, HE ;

Stamm, G .

HELVETICA CHIMICA ACTA, 1942, 25 :1162-1179

[9] EVOLUTION OF A SERIES OF PEPTIDOLEUKOTRIENE ANTAGONISTS - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF 1,6-DISUBSTITUTED INDOLES AND INDAZOLES [J].

BROWN, FJ ;

YEE, YK ;

CRONK, LA ;

HEBBEL, KC ;

KRELL, RD ;

SNYDER, DW .

JOURNAL OF MEDICINAL CHEMISTRY, 1990, 33 (06) :1771-1781

[10] HYDROXYACETOPHENONE-DERIVED ANTAGONISTS OF THE PEPTIDOLEUKOTRIENES [J].

BROWN, FJ ;

BERNSTEIN, PR ;

CRONK, LA ;

DOSSET, DL ;

HEBBEL, KC ;

MADUSKUIE, TP ;

SHAPIRO, HS ;

VACEK, EP ;

YEE, YK ;

WILLARD, AK ;

KRELL, RD ;

SNYDER, DW .

JOURNAL OF MEDICINAL CHEMISTRY, 1989, 32 (04) :807-826

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