Peer-reviewed veterinary case report
The optimization of aminooxadiazoles as orally active inhibitors of Cdc7.
- Journal:
- Bioorganic & medicinal chemistry letters
- Year:
- 2013
- Authors:
- Harrington, Paul E et al.
- Affiliation:
- Medicinal Chemistry · United States
- Species:
- rodent
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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Search related cases →Original publication: https://pubmed.ncbi.nlm.nih.gov/24120542/