Browsing by Author "Qiao, Lixin"
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Item Structure–activity relationship study of 2,4-diaminothiazoles as Cdk5/p25 kinase inhibitors(Bioorganic and Medicinal Chemistry Letters, 2012-04) Laha, Joydev K.; Zhang, Xuemei; Qiao, Lixin; Chatterjee, Snigdha; Robinson, Shaughnessy; Kosik, Kenneth S.; Cuny, Gregory D.Cdk5/p25 has emerged as a principle therapeutic target for numerous acute and chronic neurodegenerative diseases, including Alzheimer’s disease. A structure–activity relationship study of 2,4-diaminothiazole inhibitors revealed that increased Cdk5/p25 inhibitory activity could be accomplished by incorporating pyridines on the 2-amino group and addition of substituents to the 2- or 3-position of the phenyl ketone moiety. Interpretation of the SAR results for many of the analogs was aided through in silico docking with Cdk5/p25 and calculating protein hydrations sites using WaterMap. Finally, improved in vitro mouse microsomal stability was also achieved.Item Structure–activity relationship study of EphB3 receptor tyrosine kinase inhibitors(Bioorganic and Medicinal Chemistry Letters, 2010-11) Qiao, Lixin; Choi, Sungwoon; Case, April; Gainer, Thomas G.; Seyb, Kathleen I.; Glicksman, Marcie A.; Lo, Donald, C.; Stein, Ross L.; Cuny, Gregory D.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.