Development of N-2,4-pyrimidine-N-phenyl-N′-alky ureas as orally active inhibitors of tumor necrosis factor alpha (TNF-α) synthesis.: Part 2

被引：8

作者：

Maier, Jennifer A. ^{[1
]}

Brugel, Todd A. ^{[1
]}

Clark, Michael P. ^{[1
]}

Sabat, Mark ^{[1
]}

Golebiowski, Adam ^{[1
]}

Bookland, Roger G. ^{[1
]}

Laufersweiler, Matthew J. ^{[1
]}

Laughlin, Steven K. ^{[1
]}

VanRens, John C. ^{[1
]}

De, Biswanath ^{[1
]}

Hsieh, Lily C. ^{[1
]}

Brown, Kimberly K. ^{[1
]}

Juergens, Karen ^{[1
]}

Walter, Richard L. ^{[1
]}

Janusz, Michael J. ^{[1
]}

机构：

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 13期

关键词：

cytokine synthesis inhibitors; p38 alpha kinase; urea;

D O I：

10.1016/j.bmcl.2006.03.096

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on a N-2,4-pyrimidine-N-phenyl-N'-alkyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-a production. Two analogs were tested in an in vivo rat iodoacetate model of osteoarthritis and shown to be orally efficacious. X-ray co-crystallization studies with mutated p38 alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：3514 / 3518

页数：5

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