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The optimization of aminooxadiazoles as orally active inhibitors of Cdc7 |
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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 Minqing Rong Tisha San Miguel Helming Tan John G Allen |
| Institution: | 1. Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA;2. Oncology Research, Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA;3. Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA;4. Discovery Technologies, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA;5. Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA;6. Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA;7. Pharmaceutics, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA |
| 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. |
| Keywords: | Cdc7 MCM2 Kinase inhibitor Azaindole Cancer |
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