Kinesin spindle protein (KSP) inhibitors. Part 2: The design, synthesis, and characterization of 2,4-diaryl-2,5-dihydropyrrole inhibitors of the mitotic kinesin KSP

The evolution of 2,4-diaryl-2,5-dihydropyrroles as inhibitors of KSP is described. Introduction of basic amide and urea moieties to the dihydropyrrole nucleus enhanced potency and aqueous solubility, simultaneously, and provided compounds that caused mitotic arrest of A2780 human ovarian carcinoma cells with EC50s < 10 nM. Ancillary hERG activity was evaluated for this series of inhibitors.

Graphical abstract2,4-Diaryl-2,5-dihydropyrroles are reported as potent inhibitors of the mitotic kinesin KSP.Figure optionsDownload full-size imageDownload as PowerPoint slide