Discovery of Potent and Highly Selective c-Met Inhibitors for Oncology Applications

• 作 者: J.JeanCui;
• 机 构: Pfizer,Inc.USA
• 出 处: 中国上海第七届国际新药发明科技年会
• 发表日期: 2009年期

　　c-Met receptor tyrosine kinase is an attractive oncology target due to the critical role of aberrant HGF/c-Met signaling in human oncogenesis and tumor invasion/metastasis.PHA-665752 was the first reported potent and selective c-Met inhibitor.The co-crystal structure of PHA-665752 revealed a unique binding environment of c-Met kinase domain,which was used to design the second generation of c-Met inhibitor with better drug-like properties.2-Amino-5-aryl-3-benzyloxypyridine series was designed as a mimic of PHA-665752 with 2-aminopyridine replacing oxindole as a hinge binder.The 3-benzyloxy group was designed to reach the same hydrophobic pocket occupied by 2,6-dichlorophenyl group in PHA-665752,however,from a more direct angle which permitted less molecular weight and conformational constrain.The design approach was validated first with compound 1,which showed good enzymatic activity and weak cell potency.Medicinal chemistry optimization led to 2,6-dichloro-3-fluoro-α-methyl-benzyl group as an important component for c-Met cell potency,exemplified in compound 2.Further lead optimization at the aminopyridine 5-position generated clinic candidate PF-2341066,which demonstrated potent in vitro and in vivo c-Met/ALK inhibition,effective tumor growth inhibition,and good pharmaceutical properties.