Kinesin spindle protein (KSP) inhibitors. Part 6: Design and synthesis of 3,5-diaryl-4,5-dihydropyrazole amides as potent inhibitors of the mitotic kinesin KSP

3,5-Diaryl-4,5-dihydropyrazoles were discovered to be potent KSP inhibitors with excellent in vivo potency. These enzyme inhibitors possess desirable physical properties that can be readily modified by incorporation of a weakly basic amine. Careful adjustment of amine basicity was essential for preserving cellular potency in a multidrug resistant cell line while maintaining good aqueous solubility.

Graphical abstractDihydropyrazole amides such as 24 are potent inhibitors of KSP with favorable physical properties, pharmacokinetics, and in vivo potency. A diastereoselective synthesis of 24 is described.Figure optionsDownload full-size imageDownload as PowerPoint slide