Inhibitors of the tyrosine kinase EphB4. Part 3: identification of non-benzodioxole-based kinase inhibitors.

Article Details

Citation

Bardelle C, Barlaam B, Brooks N, Coleman T, Cross D, Ducray R, Green I, Brempt CL, Olivier A, Read J

Inhibitors of the tyrosine kinase EphB4. Part 3: identification of non-benzodioxole-based kinase inhibitors.

Bioorg Med Chem Lett. 2010 Nov 1;20(21):6242-5. doi: 10.1016/j.bmcl.2010.08.100. Epub 2010 Sep 16.

PubMed ID
20850301 [ View in PubMed
]
Abstract

Starting from the initial bis-anilinopyrimidine 1, good potency against EphB4 was retained when benzodioxole at C-4 was replaced by an indazole. The key interactions of the indazole with the protein were characterised by crystallographic studies. Further optimisation led to compound 20, a potent inhibitor of the EphB4 and Src kinases with good pharmacokinetics in various preclinical species and high fraction unbound in plasma. Compound 20 may be used as a tool for evaluating the potential of EphB4 kinase inhibitors in vivo.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
N'-(5-chloro-1,3-benzodioxol-4-yl)-N-(3-methylsulfonylphenyl)pyrimidine-2,4-diamineEphrin type-B receptor 4IC 50 (nM)25N/AN/ADetails
N'-(5-chloro-1,3-benzodioxol-4-yl)-N-(3-methylsulfonylphenyl)pyrimidine-2,4-diamineEphrin type-B receptor 4IC 50 (nM)187N/AN/ADetails