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作为肿瘤坏死因子α（TNF-α）合成抑制剂的N-2,4-嘧啶-N-苯基-N'-苯基脲的开发。第1部分。

Development of N-2,4-pyrimidine-N-phenyl-N'-phenyl ureas as inhibitors of tumor necrosis factor alpha (TNF-alpha) synthesis. Part 1.

作者信息

Brugel Todd A, Maier Jennifer A, Clark Michael P, Sabat Mark, Golebiowski Adam, Bookland Roger G, Laufersweiler Matthew J, Laughlin Steven K, Vanrens John C, De Biswanath, Hsieh Lily C, Mekel Marlene J, Janusz Michael J

机构信息

Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd., Mason, OH 45040, USA.

出版信息

Bioorg Med Chem Lett. 2006 Jul 1;16(13):3510-3. doi: 10.1016/j.bmcl.2006.03.095. Epub 2006 May 2.

DOI:10.1016/j.bmcl.2006.03.095
PMID:16632356
Abstract

A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on an N-2,4-pyrimidine-N-phenyl-N'-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-alpha production. X-ray co-crystallization studies with mutated p38alpha 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.

摘要

描述了一类基于N-2,4-嘧啶-N-苯基-N'-苯基脲支架的新型肿瘤坏死因子α（TNF-α）合成抑制剂。这些化合物中的许多对脂多糖刺激的TNF-α产生表现出低纳摩尔活性。对突变型p38α进行的X射线共结晶研究表明，这些三取代脲以由分子内氢键相互作用导致的假双环构象与ATP结合口袋相互作用。

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Development of N-2,4-pyrimidine-N-phenyl-N'-phenyl ureas as inhibitors of tumor necrosis factor alpha (TNF-alpha) synthesis. Part 1.作为肿瘤坏死因子α（TNF-α）合成抑制剂的N-2,4-嘧啶-N-苯基-N'-苯基脲的开发。第1部分。
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