The development of novel inhibitors of tumor necrosis factor-α (TNF-α) production based on substituted [5,5]-bicyclic pyrazolones

被引：21

作者：

Laufersweiler, MJ ^{[1
]}

Brugel, TA ^{[1
]}

Clark, MP ^{[1
]}

Goleblowski, A ^{[1
]}

Bookland, RG ^{[1
]}

Laughlin, SK ^{[1
]}

Sabat, MP ^{[1
]}

Townes, JA ^{[1
]}

VanRens, JC ^{[1
]}

De, B ^{[1
]}

Hsieh, LC ^{[1
]}

Heitmeyer, SA ^{[1
]}

Juergens, K ^{[1
]}

Brown, KK ^{[1
]}

Mekel, MJ ^{[1
]}

Walter, RL ^{[1
]}

Janusz, MJ ^{[1
]}

机构：

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 16期

关键词：

TNF-alpha; cytokine synthesis inhibition; pyrazolones; p38; kinases;

D O I：

10.1016/j.bmcl.2004.06.001

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Novel substituted [5,5]-bicyclic pyrzazolones are presented as inhibitors of tumor necrosis factor-alpha (TNF-alpha) production. Many of these compounds show low nanomolar activity against lipopolysaccaride (LPS)-induced TNF-alpha production in THP-1 cells. This class of molecules was co-crystallized with mutated p38, and several analogs showed good oral bioavailability in the rat. Oral activity of these compounds in the rat iodoacetate model for osteoarthritis is discussed. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：4267 / 4272

页数：6

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