N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck:: Indazoles as phenol isosteres with improved pharmacokinetics
N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck:: Indazoles as phenol isosteres with improved pharmacokinetics
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DOI：
10.1016/j.bmcl.2007.04.029
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发表时间：
2007-08-01
影响因子：
2.7
通讯作者：
Washington, Melanie
中科院分区：
文献类型：
--
作者：
Bamborough, Paul;Angell, Richard M.;Washington, Melanie
2,4-二硅嘧啶嘧啶是酪氨酸激酶（包括淋巴细胞特异性激酶（LEK））的众所周知的抑制剂。讨论并合理化了4位的结构活性关系。带有2-甲基-5-羟基苯胺取代基的实例特别有效，但表现出较差的口服药代动力学。 4-氨基（5methyl-ih-吲唑）取代这种取代基产生了具有可比酶效力并改善药代动力学特性的化合物。 （c）2007 Elsevier Ltd.保留所有权利。
2,4-Dianilino pyrimidines are well-known inhibitors of tyrosine kinases including lymphocyte specific kinase (Lek). Structure-activity relationships at the 4-position are discussed and rationalised. Examples bearing a 2-methyl-5-hydroxyaniline substituent at the 4-position were especially potent but showed poor oral pharmacokinetics. Replacement of this substituent by 4-amino(5methyl-IH-indazole) yielded compounds with comparable enzyme potency and improved pharmacokinetic properties. (c) 2007 Elsevier Ltd. All rights reserved.