| Literature DB >> 24120542 |
Paul E Harrington1, Matthew P Bourbeau, Christopher Fotsch, Michael Frohn, Alexander J Pickrell, Andreas Reichelt, Kelvin Sham, Aaron C Siegmund, Julie M Bailis, Tammy Bush, Sonia Escobar, Dean Hickman, Scott Heller, Faye Hsieh, Jessica N Orf, Minqing Rong, Tisha San Miguel, Helming Tan, Leeanne Zalameda, John G Allen.
Abstract
A series of aminooxadiazoles was optimized for inhibition of Cdc7. Early lead isoquinoline 1 suffered from modest cell potency (cellular IC50=0.71 μM measuring pMCM2), low selectivity against structurally related kinases, and high IV clearance in rats (CL=18 L/h/kg). Extensive optimization resulted in azaindole 26 (Cdc7 IC50=1.1 nM, pMCM2 IC50=32 nM) that demonstrated robust lowering of pMCM2 in a mouse pharmacodynamic (PD) model when dosed orally. Modifications to improve the pharmacokinetic profile of this series were guided by trapping experiments with glutathione in rat hepatocytes.Entities:
Keywords: Azaindole; Cancer; Cdc7; Kinase inhibitor; MCM2
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Year: 2013 PMID： 24120542 DOI： 10.1016/j.bmcl.2013.09.055
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823