发现具有噻吩并[2,3-d]嘧啶或呋喃并[2,3-d]嘧啶骨架的新型 c-Met 激酶抑制剂。
Discovery of novel c-Met kinase inhibitors bearing a thieno[2,3-d]pyrimidine or furo[2,3-d]pyrimidine scaffold.
机构信息
Synthetic Organic and Medicinal Chemistry Laboratory (SOMCL), State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China.
出版信息
Bioorg Med Chem. 2011 Jul 1;19(13):3906-18. doi: 10.1016/j.bmc.2011.05.038. Epub 2011 May 24.
A series of thieno[2,3-d]pyrimidines and furo[2,3-d]pyrimidines were synthesized and evaluated for the c-Met inhibition. Thieno[2,3-d]pyrimidine 6b stood out as the most potent showing an IC(50) of 35.7 nM. This compound displayed high inhibitory effect on cell proliferation in BaF3-TPR-Met cells and showed high selectivity for c-Met family against other 14 tested kinases. However, compound 6b was found ineffective in the c-Met-dependent U-87MG human gliobastoma xenograft model that may be relevant to its poor PK profile.
一系列噻吩并[2,3-d]嘧啶和呋喃并[2,3-d]嘧啶被合成并评估了对 c-Met 的抑制作用。噻吩并[2,3-d]嘧啶 6b 表现出最强的活性，IC50 为 35.7 nM。该化合物对 BaF3-TPR-Met 细胞中的细胞增殖具有高抑制作用，并对 c-Met 家族表现出高选择性，而对其他 14 种测试的激酶则表现出低选择性。然而，化合物 6b 在 c-Met 依赖性 U-87MG 人神经胶质瘤异种移植模型中无效，这可能与其较差的 PK 特征有关。
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