Kinesin spindle protein (KSP) inhibitors. Part 8: Design and synthesis of 1,4-diaryl-4,5-dihydropyrazoles as potent inhibitors of the mitotic kinesin KSP

1,4-Diaryl-4,5-dihydropyrazoles (i.e., 25) are reported as potent inhibitors of the mitotic kinesin KSP. Inspired by previous efforts in the pyrazolobenzoxazine class of KSP inhibitors, the design and synthesis of 1,4-diaryl-4,5-dihydropyrazole inhibitors of KSP are described. Crystallographic evide...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2007-10, Vol.17 (20), p.5677-5682
Hauptverfasser:	Roecker, Anthony J., Coleman, Paul J., Mercer, Swati P., Schreier, John D., Buser, Carolyn A., Walsh, Eileen S., Hamilton, Kelly, Lobell, Robert B., Tao, Weikang, Diehl, Ronald E., South, Vicki J., Davide, Joseph P., Kohl, Nancy E., Yan, Youwei, Kuo, Lawrence C., Li, Chunze, Fernandez-Metzler, Carmen, Mahan, Elizabeth A., Prueksaritanont, Thomayant, Hartman, George D.
Format:	Artikel
Sprache:	eng
Schlagworte:	1,4-Diaryl-4,5-dihydropyrazoles Antimitotics Binding Sites Cancer Copper-mediated N-arylation Crystallography, X-Ray Drug Design Humans Hydrogen - chemistry Kinesin - antagonists & inhibitors Kinesin - metabolism Kinesin spindle protein Kinesins KSP inhibitors Mitosis - drug effects Models, Molecular Molecular Structure Pgp Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacology Structure-Activity Relationship
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Zusammenfassung:	1,4-Diaryl-4,5-dihydropyrazoles (i.e., 25) are reported as potent inhibitors of the mitotic kinesin KSP. Inspired by previous efforts in the pyrazolobenzoxazine class of KSP inhibitors, the design and synthesis of 1,4-diaryl-4,5-dihydropyrazole inhibitors of KSP are described. Crystallographic evidence of binding mode and in vivo potency data is also highlighted.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2007.07.074