New cyclooxygenase-2/5-lipoxygenase inhibitors.: 1.: 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran derivatives as gastrointestinal safe antiinflammatory and analgesic agents:: Discovery and variation of the 5-keto substituent

被引：61

作者：

Janusz, JM ^{[1
]}

Young, PA ^{[1
]}

Ridgeway, JM ^{[1
]}

Scherz, MW ^{[1
]}

Enzweiler, K ^{[1
]}

Wu, LI ^{[1
]}

Gan, LX ^{[1
]}

Darolia, R ^{[1
]}

Matthews, RS ^{[1
]}

Hennes, D ^{[1
]}

Kellstein, DE ^{[1
]}

Green, SA ^{[1
]}

Tulich, JL ^{[1
]}

Rosario-Jansen, T ^{[1
]}

Magrisso, IJ ^{[1
]}

Wehmeyer, KR ^{[1
]}

Kuhlenbeck, DL ^{[1
]}

Eichhold, TH ^{[1
]}

Dobson, RLM ^{[1
]}

Sirko, SP ^{[1
]}

Farmer, RW ^{[1
]}

机构：

[1] Procter & Gamble Pharmaceut, Hlth Care Res Ctr, Mason, OH 45040 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1998年 / 41卷 / 07期

关键词：

D O I：

10.1021/jm970679q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 5-keto-substituted 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofurans (DHDMBFs) were prepared and evaluated as potential nonsteroidal antiinflammatory and analgesic agents. Interest in this class of compounds arose when a DHDMBF was found to be an active metabolite of the di-tert-butylphenol antiinflammatory agent tebufelone. We have now found that a variety of 5-keto-substituted DHDMBFs have good in vivo antiinflammatory and analgesic activity after oral administration. These compounds inhibit both cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) in vitro. The cyclooxygenase inhibition was found to be selective for the cyclooxygenase-2 isoform, and this combination of COX-2/5-LOX inhibition may be responsible for the gastrointestinal safety of compounds such as 30.

引用

页码：1112 / 1123

页数：12

共 30 条

[1]

[Anonymous], 1985, NONSTEROIDAL ANTIINF

[2]

[Anonymous], DRUGS NEWS PERSPECT

[3] INDOMETHACIN-INDUCED LEUKOCYTE ADHESION IN MESENTERIC VENULES - ROLE OF LIPOXYGENASE PRODUCTS [J].

ASAKO, H ;

KUBES, P ;

WALLACE, J ;

GAGINELLA, T ;

WOLF, RE ;

GRANGER, DN .

AMERICAN JOURNAL OF PHYSIOLOGY, 1992, 262 (05) :G903-G908

[4] HYPOPHOSPHOROUS ACID AND ITS SALTS - NEW REAGENTS FOR RADICAL CHAIN DEOXYGENATION, DEHALOGENATION AND DEAMINATION [J].

BARTON, DHR ;

JANG, DO ;

JASZBERENYI, JC .

TETRAHEDRON LETTERS, 1992, 33 (39) :5709-5712

[5] THE INVENTION OF RADICAL REACTIONS .32. RADICAL DEOXYGENATIONS, DEHALOGENATIONS, AND DEAMINATIONS WITH DIALKYL PHOSPHITES AND HYPOPHOSPHOROUS ACID AS HYDROGEN SOURCES [J].

BARTON, DHR ;

JANG, DO ;

JASZBERENYI, JC .

JOURNAL OF ORGANIC CHEMISTRY, 1993, 58 (24) :6838-6842

[6]

DEMONTELLANO PRO, 1983, ANNU REV PHARMACOL, V23, P481

[7] NS-398, A NEW ANTIINFLAMMATORY AGENT, SELECTIVELY INHIBITS PROSTAGLANDIN-G/H SYNTHASE CYCLOOXYGENASE (COX-2) ACTIVITY IN-VITRO [J].

FUTAKI, N ;

TAKAHASHI, S ;

YOKOYAMA, M ;

ARAI, I ;

HIGUCHI, S ;

OTOMO, S .

PROSTAGLANDINS, 1994, 47 (01) :55-59

[8] NS-398, A NOVEL NONSTEROIDAL ANTIINFLAMMATORY DRUG WITH POTENT ANALGESIC AND ANTIPYRETIC EFFECTS, WHICH CAUSES MINIMAL STOMACH LESIONS [J].

FUTAKI, N ;

YOSHIKAWA, K ;

HAMASAKA, Y ;

ARAI, I ;

HIGUCHI, S ;

IIZUKA, H ;

OTOMO, S .

GENERAL PHARMACOLOGY, 1993, 24 (01) :105-110

[9]

GIBSON TW, 1982, J ORG CHEM, V47, P2278

[10] PHARMACOLOGICAL PROPERTIES OF A NEW ANTI-INFLAMMATORY COMPOUND, ALPHA-(3,5-DI-TERT-BUTYL-4-HYDROXYBENZYLIDENE)-GAMMA-BUTYROLACTONE (KME-4), AND ITS INHIBITORY EFFECTS ON PROSTAGLANDIN SYNTHETASE AND 5-LIPOXYGENASE [J].

HIDAKA, T ;

HOSOE, K ;

ARIKI, Y ;

TAKEO, K ;

YAMASHITA, T ;

KATSUMI, I ;

KONDO, H ;

YAMASHITA, K ;

WATANABE, K .

JAPANESE JOURNAL OF PHARMACOLOGY, 1984, 36 (01) :77-85

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