Design, synthesis, and biological evaluation of phenylamino-substituted 6,11-dihydro-dibenzo[b,e]oxepin-11-ones and dibenzo[a,d]cycloheptan-5-ones:: Novel p38 MAP kinase inhibitors

被引：40

作者：

Laufer, Stefan A. ^{[1
]}

Ahrens, Gabriele M. ^{[1
]}

Karcher, Solveigh C. ^{[1
]}

Hering, Joerg S. ^{[1
]}

Niess, Raimund ^{[1
]}

机构：

[1] Univ Tubingen, Dept Pharmaceut & Med Chem, Inst Pharm, D-72076 Tubingen, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 26期

关键词：

D O I：

10.1021/jm061072p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The pathogenesis of chronic inflammatory diseases is promoted by various pro-inflammatory cytokines. p38 MAP kinase seems to be a valid target as it controls proinflammatory cytokine levels on both transcriptional and translational levels. Starting from benzophenone-type inhibitors, a rigidisation strategy lead to 3-amino-6,11-dihydro-dibenzo[b,e]thiepin-11-one, phenylamino-substituted 6,11-dihydro-dibenzo[b,e]oxepin-11-ones, and dibenzo[a,d]cyclohepten-5-ones. Synthesis, p38 inhibition, and CYP-inhibition of selected compounds are described.

引用

页码：7912 / 7915

页数：4

共 15 条

[1]

Adams JL, 2001, PROGR MED CHEM, V38, P1, DOI 10.1016/S0079-6468(08)70091-2

[2]

Cirillo Pier F., 2002, Current Topics in Medicinal Chemistry, V2, P1021, DOI 10.2174/1568026023393390

[3]

EICHER T, 1988, SYNTHESIS-STUTTGART, P525

[4] Acquisition of sensitivity of stress-activated protein kinases to the p38 inhibitor, SB 203580, by alteration of one or more amino acids within the ATP binding pocket [J].

Gum, RJ ;

McLaughlin, MM ;

Kumar, S ;

Wang, ZL ;

Bower, MJ ;

Lee, JC ;

Adams, JL ;

Livi, GP ;

Goldsmith, EJ ;

Young, PR .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (25) :15605-15610

[5] TRICYCLIC ARYL-SUBSTITUTED ANTICOCCIDIAL AZAURACILS [J].

KLUGE, AF ;

CAROON, JM ;

UNGER, SH ;

RYLEY, JF .

JOURNAL OF MEDICINAL CHEMISTRY, 1978, 21 (06) :529-536

[6] Pyridinylimidazole compound SB 203580 inhibits the activity but not the activation of p38 mitogen-activated protein kinase [J].

Kumar, S ;

Jiang, MS ;

Adams, JL ;

Lee, JC .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1999, 263 (03) :825-831

[7] p38 map kinases: Key signalling molecules as therapeutic targets for inflammatory diseases [J].

Kumar, S ;

Boehm, J ;

Lee, JC .

NATURE REVIEWS DRUG DISCOVERY, 2003, 2 (09) :717-726

[8] An immunosorbent, nonradioactive p38 MAP kinase assay comparable to standard radioactive liquid-phase assays [J].

Laufer, S ;

Thuma, S ;

Peifer, C ;

Greim, C ;

Herweh, Y ;

Albrecht, A ;

Dehner, F .

ANALYTICAL BIOCHEMISTRY, 2005, 344 (01) :135-137

[9] Synthesis and structure-activity relationship of aminobenzophenones.: A novel class of p38 MAP kinase inhibitors with high antiinflammatory activity [J].

Ottosen, ER ;

Sorensen, MD ;

Björkling, F ;

Skak-Nielsen, T ;

Fjording, MS ;

Aaes, H ;

Binderup, L .

JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (26) :5651-5662

[10] Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site [J].

Pargellis, C ;

Tong, L ;

Churchill, L ;

Cirillo, PF ;

Gilmore, T ;

Graham, AG ;

Grob, PM ;

Hickey, ER ;

Moss, N ;

Pav, S ;

Regan, J .

NATURE STRUCTURAL BIOLOGY, 2002, 9 (04) :268-272

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