Structure–activity relationship study of EphB3 receptor tyrosine kinase inhibitors


A structure–activity relationship study for a 2-chloroanilide derivative of pyrazolo[1,5-a]pyridine revealed that increased EphB3 kinase inhibitory activity could be accomplished by retaining the 2-chloroanilide and introducing a phenyl or small electron donating substituents to the 5-position of the pyrazolo[1,5-a]pyridine. In addition, replacement of the pyrazolo[1,5-a]pyridine with imidazo[1,2-a]pyridine was well tolerated and resulted in enhanced mouse liver microsome stability. The structure–activity relationship for EphB3 inhibition of both heterocyclic series was similar. Kinase inhibitory activity was also demonstrated for representative analogs in cell culture. An analog (32, LDN-211904) was also profiled for inhibitory activity against a panel of 288 kinases and found to be quite selective for tyrosine kinases. Overall, these studies provide useful molecular probes for examining the in vitro, cellular and potentially in vivo kinase-dependent function of EphB3 receptor.



structure-activity relationship, EphB3, Kinase, Inhibitor, Microsomal stability


Copyright 2009 Bioorganic and Medicinal Chemistry Letters. This is a post-print versoin of a published paper that is available at: Recommended citation: Qiao, Lixin, Sungwoon Choi, April Case, Thomas G. Gainer, Kathleen Seyb, Marcie A. Glicksman, Donald C. Lo, Ross L. Stein, and Gregory D. Cuny. "Structure–activity relationship study of EphB3 receptor tyrosine kinase inhibitors." Bioorganic & medicinal chemistry letters 19, no. 21 (2009): 6122-6126. doi: 10.1016/j.bmcl.2009.09.010. This item has been deposited in accordance with publisher copyright and licensing terms and with author's permission.