New 2-amino-(5-cyanothiazol-2-yl) pyridines: KDR inhibitors with improved pharmacokinetic profile

Abstract

In both animal and human settings, inhibition of the vascular endothelial growth factor (VEGF) pathway has proven to be a valuable approach to reduce tumour growth by limiting the formation of new capillaries from existing vasculature (angiogenesis). Endothelial cell proliferation and migration, two critical steps in angiogenesis, are mediated through a specific VEGF receptor, the kinase insert domain-containing receptor (KDR), expressed at the cell surface. Over the past few years, the search for small molecule inhibitors of the kinase activity of this receptor has been a very active area leading to the discovery of a variety of chemical leads, several of which are undergoing evaluation in clinical trials. Merck has been very involved in this field, delivering chemically diverse KDR inhibitors. In this patent application, a team from Merck discloses 2-amino-(5-cyanothiazol-2-yl)pyridines. Members of this class of inhibitors possess improved pharmacokinetics.

• angiogenesis
• cancer
• kinase inhibitor
• kinase insert domain-containing receptor (KDR)
• thiazole
• vascular endothelial growth factor (VEGF)