具有优异体内疗效的强效且选择性基于2-氨基苯并咪唑的p38α丝裂原活化蛋白激酶抑制剂的设计
Design of potent and selective 2-aminobenzimidazole-based p38alpha MAP kinase inhibitors with excellent in vivo efficacy.
作者信息
de Dios Alfonso, Shih Chuan, López de Uralde Beatriz, Sánchez Concepción, del Prado Miriam, Martín Cabrejas Luisa M, Pleite Sehila, Blanco-Urgoiti Jaime, Lorite María José, Nevill C Richard, Bonjouklian Rosanne, York Jeremy, Vieth Michal, Wang Yong, Magnus Nicholas, Campbell Robert M, Anderson Bryan D, McCann Denis J, Giera Deborah D, Lee Paul A, Schultz Richard M, Li Li C, Johnson Lea M, Wolos Jeffrey A
机构信息
Eli Lilly and Co., Lilly S.A., Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain.
出版信息
J Med Chem. 2005 Apr 7;48(7):2270-3. doi: 10.1021/jm048978k.
We report the design and discovery of a 2-aminobenzimidazole-based series of potent and highly selective p38alphainhibitors. The lead compound 1 had low-nanomolar activity in both ATP competitive enzyme binding and inhibition of TNFalpha release in macrophages. Compound 18 showed excellent pharmacokinetics properties and oral activity in the rat collagen induced arthritis model compared with other p38 reference compounds. A SAR strategy to address CyP3A4 liability is also described.
我们报告了一系列基于2-氨基苯并咪唑的高效且高选择性p38α抑制剂的设计与发现。先导化合物1在ATP竞争性酶结合以及抑制巨噬细胞中TNFα释放方面均具有低纳摩尔活性。与其他p38参考化合物相比，化合物18在大鼠胶原诱导性关节炎模型中表现出优异的药代动力学性质和口服活性。还描述了一种应对细胞色素P450 3A4（CYP3A4）相关问题的构效关系策略。
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