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

R M Garbaccio ,Weikang Tao,Carolyn A Buser,Michael D Schaber,Kenneth L Arrington,Edward S Tasber,Robert B Lobell,Vicki J South,William F Hoffman,Mark E Fraley,Thomayant Prueksaritanont,Cathy Shu,Maricel Torrent,Hans E Huber,George D Hartman,Eileen S Walsh,Lawrence C Kuo,Christy M Olson,Kelly Hamilton,Nancy E Kohl,Christine Fernandes,David Heimbrook ,Donald Slaughter ,Yong-Bin Yan

doi:10.1016/j.bmcl.2005.12.094

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

R M Garbaccio , Weikang Tao + Show 22 more

https://doi.org/10.1016/j.bmcl.2005.12.094

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Journal: Bioorganic & Medicinal Chemistry Letters	Publication Date: Jan 24, 2006
Citations: 52

Affiliation: United States Military Academy

#Kinesin Spindle Protein #Kinesin Spindle Protein Inhibitors + Show 8 more

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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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