Kinesin spindle protein (KSP) belongs to the kinesin-5 family and is necessary for the formation of the bipolar mitotic spindle. Inhibition of this motor enzyme has been validated to result in mitotic arrest and apoptosis. Many reported KSP inhibitors are currently being tested in clinical trials for the treatment of cancer. However, these potential anti-cancer agents are delivered intravenously utilizing a variety of dosing schedules. Accordingly, the development of an orally bioavailable small molecule KSP inhibitor represents a promising means of providing a more convenient dosing schedule.A medicinal chemistry effort to discover small molecule inhibitors of KSP was initiated following the disclosure of 3,5-diaryl-4,5-dihydropyrazole 1  and related analogues. Inspired by its potent biological activity, we were encouraged to envision compound 1 to serve as our initial structural platform from which to access a range of spiro-fused-5-membered ring scaffolds. This presentation will describe the synthesis, structure activity relationships, pharmacokinetic and pharmacological properties of these potent KSP inhibitors.

Design, synthesis, and biological evaluation of spiro-fused thiadiazoline inhibitors of the mitotic kinesin KSP

248th National Meeting (2014)

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