JNJ-17029259

The growth and metastasis of solid tumors are dependent on angiogenesis.The vascular endothelial growth factor (VEGF) is of particular interest since it is essential for angiogenesis.The development of novel inhibitors of VEGF receptor type 2 (VEGFR-2) is important.Quant. structure-activity relationship (QSAR) studies were performed to understand the structural factors affecting inhibitory potency of 4-aryl-5-cyano-2-aminopyrimidines.Docking studies were performed to explore the binding mode between all of the inhibitors and the VEGFR-2 and produce the bioactive conformation of each compound in the whole dataset.The docked conformer-based alignment strategy gave the 3D-QSAR models.Both CoMFA (q² = 0.575, r² = 0.903, and r²_predictive = 0.763) and CoMSIA (q² = 0.617, r² = 0.869, and r²_predictive = 0.783) gave reasonable results.The contour maps obtained from 3D-QSAR studies were evaluated for activity trends for the mols. analyzed.CoMSIA models exhibited good external predictability as compared with that of CoMFA models.The data generated from the present study helped us to predict the activity of new inhibitors and further design some novel and potent VEGFR-2 enzyme inhibitors.

The fundamental role that receptor tyrosine kinases play in cancer and other proliferative diseases has provided the impetus for an extensive effort to develop multikinase inhibitors. In this study three dimensional Pharmacophore models were developed using recently synthesized KDR and Tie‐2 receptor tyrosine kinase inhibitors by using CATALYST HypoGen program. The high cost difference (68.098 for KDR and 46.971 for Tie‐2), good correlation coefficient (0.948 for KDR and 0.963 for Tie‐2) and low root mean square deviation (0.871 for KDR and 0.668 for Tie‐2) suggest that highly predictive pharmacophore models were successfully obtained. The models were further validated by two methods, first by using test set compounds (305 for KDR and 131 for Tie‐2) which resulted a correlation of 0.606 for KDR and 0.706 for Tie‐2 between HypoGen estimated activities vs. experimental activities and secondly by fischer randomization test. The application of the validated pharmacophore models shows great success in screening in‐house database and predicted 61compounds with multikinase activity.