ITK 的苯并咪唑抑制剂的从靶点到先导物的研究：一类新型激酶抑制剂的发现
Hit-to-lead studies on benzimidazole inhibitors of ITK: discovery of a novel class of kinase inhibitors.
作者信息
Snow Roger J, Abeywardane Asitha, Campbell Scot, Lord John, Kashem Mohammed A, Khine Hnin Hnin, King Josephine, Kowalski Jennifer A, Pullen Steven S, Roma Teresa, Roth Gregory P, Sarko Christopher R, Wilson Noel S, Winters Michael P, Wolak John P, Cywin Charles L
机构信息
Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA.
出版信息
Bioorg Med Chem Lett. 2007 Jul 1;17(13):3660-5. doi: 10.1016/j.bmcl.2007.04.045. Epub 2007 Apr 25.
Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed.
苯并咪唑1通过高通量筛选被鉴定为ITK的选择性抑制剂。从活性化合物到先导化合物的研究确定了所有三个取代基的构效关系。在C6处反转酰胺键得到化合物16，其活性提高了五倍。这种增强作用可通过取代基的构象偏好来解释。本文提出了苯并咪唑类化合物与ITK的ATP结合位点结合的模型。
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