N-2,4-嘧啶-N-苯基-N'-烷基脲作为肿瘤坏死因子α（TNF-α）合成的口服活性抑制剂的研发。第2部分。

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

作者信息

Maier Jennifer A, Brugel Todd 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, Brown Kimberly K, Juergens Karen, Walter Richard L, Janusz Michael J

机构信息

Procter & 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):3514-8. doi: 10.1016/j.bmcl.2006.03.096. Epub 2006 Apr 24.

DOI:10.1016/j.bmcl.2006.03.096

PMID:16632350

Abstract

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-alpha 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 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'-烷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。两种类似物在骨关节炎的体内大鼠碘乙酸模型中进行了测试，结果显示口服有效。与突变的p38α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产生的假双环构象与ATP结合口袋相互作用。