Kinesin spindle protein (KSP) inhibitors. Part 3: synthesis and evaluation of phenolic 2,4-diaryl-2,5-dihydropyrroles with reduced hERG binding and employment of a phosphate prodrug strategy for aqueous solubility |
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| Authors: | Garbaccio Robert M Fraley Mark E Tasber Edward S Olson Christy M Hoffman William F Arrington Kenneth L Torrent Maricel Buser Carolyn A Walsh Eileen S Hamilton Kelly Schaber Michael D Fernandes Christine Lobell Robert B Tao Weikang South Vicki J Yan Youwei Kuo Lawrence C Prueksaritanont Thomayant Slaughter Donald E Shu Cathy Heimbrook David C Kohl Nancy E Huber Hans E Hartman George D |
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| Institution: | Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. robert_garbaccio@merck.com |
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| Abstract: | 2,4-Diaryl-2,5-dihydropyrroles have been discovered to be novel, potent and water-soluble inhibitors of KSP, an emerging therapeutic target for the treatment of cancer. A potential concern for these basic KSP inhibitors (1 and 2) was hERG binding that can be minimized by incorporation of a potency-enhancing C2 phenol combined with neutral N1 side chains. Aqueous solubility was restored to these, and other, non-basic inhibitors, through a phosphate prodrug strategy. |
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