| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 10591318 | Bioorganic & Medicinal Chemistry Letters | 2013 | 5 Pages |
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.
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Authors
Paul E. Harrington, 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,