Zhu Tong, Yan Zheng, Chucholowski Alexander, Webb Thomas R, Li Rongshi
Department of High Throughput Medicinal Chemistry, ChemBridge Research Laboratories, San Diego, California 92127, USA.
J Comb Chem. 2006 May-Jun;8(3):401-9. doi: 10.1021/cc060018r.
The optimization of screening hits on a promising new target for therapy of certain cancers involving anaplastic lymphoma kinase (ALK) inspired the development of this efficient solid-phase chemistry. A series of novel pyridones have been recently discovered as inhibitors of ALK, which led to the design of focused libraries around the pyridone scaffold. A stepwise process involving iterative template modification based on both medicinal chemistry insights and computational ranking of virtual libraries was employed in the design. The unique solid-phase chemistry has addressed the need for rapid optimization of this "early lead" series. Herein the methodology and scope of the chemistry, as well as its application for library synthesis, are discussed.
对涉及间变性淋巴瘤激酶（ALK）的某些癌症治疗的有前景新靶点筛选命中物的优化，激发了这种高效固相化学的发展。最近发现了一系列新型吡啶酮作为ALK抑制剂，这导致围绕吡啶酮支架设计了聚焦文库。在设计中采用了一个逐步过程，该过程基于药物化学见解和虚拟文库的计算排名进行迭代模板修饰。独特的固相化学满足了对该“早期先导”系列进行快速优化的需求。本文讨论了该化学的方法和范围，以及其在文库合成中的应用。
