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 |
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Authors: | Cox Christopher D Torrent Maricel Breslin Michael J Mariano Brenda J Whitman David B Coleman Paul J Buser Carolyn A Walsh Eileen S Hamilton Kelly Schaber Michael D Lobell Robert B Tao Weikang South Vicki J Kohl Nancy E Yan Youwei Kuo Lawrence C Prueksaritanont Thomayant Slaughter Donald E Li Chunze Mahan Elizabeth Lu Bing Hartman George D |
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Institution: | Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, USA. chris_cox@merck.com |
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Abstract: | Molecular 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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