Synthesis and SAR of pyrrolotriazine-4-one based Eg5 inhibitors

Synthesis and SAR of substituted pyrrolotriazine-4-one analogues as Eg5 inhibitors are described. Many of these analogues displayed potent inhibitory activities in the Eg5 ATPase and A2780 cell proliferation assays. In addition, pyrrolotriazine-4-one analogue 26 demonstrated in vivo efficacy in an iv P388 murine leukemia model. Both NMR and X-ray crystallographic studies revealed that these analogues bind to an allosteric site on the Eg5 protein.

Graphical abstractSynthesis and SAR of substituted pyrrolotriazine-4-one analogues as Eg5 inhibitors are described. Analogue 26 demonstrated in vivo efficacy in an iv P388 murine leukemia model.Figure optionsDownload full-size imageDownload as PowerPoint slide