Discovery of novel c-Met kinase inhibitors bearing a thieno[2,3-d]pyrimidine or furo[2,3-d]pyrimidine scaffold |
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Authors: | Zhao Ailing Gao Xin Wang Yuanxiang Ai Jing Wang Ying Chen Yi Geng Meiyu Zhang Ao |
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Institution: | 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. |
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Abstract: | A series of thieno2,3-d]pyrimidines and furo2,3-d]pyrimidines were synthesized and evaluated for the c-Met inhibition. Thieno2,3-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. |
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