Title of article :
Hit-to-lead optimization of 1,4-dihydroindeno[1,2-c]pyrazoles as a novel class of KDR kinase inhibitors
Author/Authors :
Jurgen Dinges، نويسنده , , Irini Akritopoulou-Zanze، نويسنده , , Lee D. Arnold، نويسنده , , Teresa Barlozzari، نويسنده , , Peter F. Bousquet، نويسنده , , George A. Cunha، نويسنده , , Anna M. Ericsson، نويسنده , , Nobuhiko Iwasaki، نويسنده , , Michael R. Michaelides، نويسنده , , Nobuo Ogawa، نويسنده , , Kathleen M. Phelan، نويسنده , , Paul Rafferty، نويسنده , , Thomas J. Sowin، نويسنده , , Kent D. Stewart، نويسنده , , Ryukou Tokuyama، نويسنده , , Zhiren Xia، نويسنده , , Henry Q. Zhang، نويسنده ,
Abstract :
A series of 1,4-dihydroindeno[1,2-c]pyrazoles was prepared and evaluated for their enzymatic inhibition of KDR kinase. Computer modeling studies revealed the importance of attaching a basic side chain in predicting the binding mode of those compounds. Further investigation of structure-activity relationships led to 19, a lead compound with an acceptable selectivity profile, activity in whole cells, and good oral efficacy in an estradiol-induced murine uterine edema model of VEGF activity.
Keywords :
Receptor tyrosine kinase , KDR kinase , CANCER , inhibitor , 1 , 2-c]pyrazoles
