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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

2007; Elsevier BV; Volume: 17; Issue: 19 Linguagem: Inglês

10.1016/j.bmcl.2007.07.046

1464-3405

Paul J. Coleman, John D. Schreier, Christopher D. Cox, Mark E. Fraley, R. M. Garbaccio, Carolyn A. Buser, Eileen S. Walsh, Kelly Hamilton, Robert B. Lobell, Keith Rickert, Weikang Tao, Ronald E. Diehl, Vicki J. South, Joseph P. Davide, Nancy E. Kohl, Youwei Yan, Lawrence Kuo, Thomayant Prueksaritanont, Chunze Li, Elizabeth Mahan, Carmen Fernández‐Metzler, Joseph J. Salata, George D. Hartman,

Amino Acid Enzymes and Metabolism

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.