Kinesin spindle protein (KSP) inhibitors. Part 4: Structure-based design of 5-alkylamino-3,5-diaryl-4,5-dihydropyrazoles as potent, water-soluble inhibitors of the mitotic kinesin KSP
2006; Elsevier BV; Volume: 16; Issue: 12 Linguagem: Inglês
10.1016/j.bmcl.2006.03.040
ISSN1464-3405
AutoresChristopher D. Cox, Maricel Torrent, Michael J. Breslin, Brenda J. Mariano, David B. Whitman, Paul J. Coleman, Carolyn A. Buser, Eileen S. Walsh, Kelly Hamilton, Michael D. Schaber, Robert B. Lobell, Weikang Tao, Vicki J. South, Nancy E. Kohl, Youwei Yan, Lawrence C. Kuo, Thomayant Prueksaritanont, Donald E. Slaughter, Chunze Li, Elizabeth Mahan, Bing Lu, George D. Hartman,
Tópico(s)Photosynthetic Processes and Mechanisms
ResumoMolecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound.
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