Polymer-Supported Synthesis of Pyridone-Focused Libraries as Inhibitors of Anaplastic Lymphoma Kinase

Abstract

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.