Title of article :
1,4-Dihydroindeno[1,2-c]pyrazoles as potent checkpoint kinase 1 inhibitors: Extended exploration on phenyl ring substitutions and preliminary ADME/PK studies
Author/Authors :
Yunsong Tong، نويسنده , , Akiyo Claiborne، نويسنده , , Magdalena Pyzytulinska، نويسنده , , Zhi-Fu Tao، نويسنده , , Kent D. Stewart، نويسنده , , Peter Kovar، نويسنده , , Zehan Chen، نويسنده , , Robert B. Credo، نويسنده , , Ran Guan، نويسنده , , Philip J. Merta، نويسنده , , Haiying Zhang، نويسنده , , Jennifer Bouska، نويسنده , , Elizabeth A. Everitt، نويسنده , , Bernard P. Murry، نويسنده , , Dean Hickman، نويسنده , , Tim J. Stratton، نويسنده , , Jian Wu، نويسنده , , Saul H. Rosenberg، نويسنده , , Hing L. Sham، نويسنده , , Thomas J. Sowin، نويسنده , , et al.، نويسنده ,
Abstract :
A study on substitutions at the four open positions on the phenyl ring of the 1,4-dihydroindeno[1,2-c]pyrazoles as potent CHK-1 inhibitors is described. Bis-substitution at both the 6- and 7-positions led to inhibitors with IC50 values below 0.3 nM. The compound with the best overall activities (36) was able to potentiate the anti-proliferative effect of doxorubicin in HeLa cells by at least 47-fold. Physicochemical, metabolic, and pharmacokinetic properties of selected inhibitors are also disclosed.
Keywords :
2-c]pyrazoles , Checkpoint kinase 1 inhibitors , Chk-1 inhibitors , Sensitizing DNA-damaging agents , 1
