DESIGN OF 5-(3,5-DI-TERT-BUTYL-4-HYDROXYPHENYL)-1,3,4-THIADIAZOLES, 5-(3,5-DI-TERT-BUTYL-4-HYDROXYPHENYL)-1,3,4-OXADIAZOLES, AND 5-(3,5-DI-TERT-BUTYL-4-HYDROXYPHENYL)-1,2,4-TRIAZOLES AS ORALLY-ACTIVE, NONULCEROGENIC ANTIINFLAMMATORY AGENTS

被引：461

作者：

MULLICAN, MD

WILSON, MW

CONNOR, DT

KOSTLAN, CR

SCHRIER, DJ

DYER, RD

机构：

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

[2] WARNER LAMBERT PARKE DAVIS,DIV PHARMACEUT RES,DEPT IMMUNOPATHOL,ANN ARBOR,MI 48105

[3] WARNER LAMBERT PARKE DAVIS,DIV PHARMACEUT RES,DEPT BIOCHEM,ANN ARBOR,MI 48105

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1993年 / 36卷 / 08期

关键词：

D O I：

10.1021/jm00060a017

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

To discover dual inhibitors of 5-lipoxygenase (LO) and cyclooxygenase (CO) with improved pharmacokinetic properties, we have designed and synthesized series of 1,2,4-triazole, 1,3,4-oxadiazole, and 1,3,4-thiadiazole di-tert-butylphenol derivatives which exhibit a wide range of log P (2.3 to >4) and pK(a) (5.5-12) values. From this work 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione, choline salt (12a, CI-986) was found to be a potent inhibitor of 5-LO (IC50 = 2.8 muM) and CO (IC50= 0.8 muM), orally active in rat models of inflammation and nonulcerogenic.

引用

页码：1090 / 1099

页数：10

共 36 条

[1] 2-SUBSTITUTED-1,3,4-OXA AND THIA-DIAZOLINE-5-THIONES [J].