Title of article :
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
Author/Authors :
Robert M. Garbaccio، نويسنده , , Mark E. Fraley، نويسنده , , Edward S. Tasber، نويسنده , , Christy M. Olson، نويسنده , , William F. Hoffman، نويسنده , , Kenneth L. Arrington، نويسنده , , Maricel Torrent، نويسنده , , Carolyn A. Buser، نويسنده , , Eileen S. Walsh، نويسنده , , Kelly Hamilton، نويسنده , , Michael D. Schaber، نويسنده , , Christine Fernandes، نويسنده , , Robert B. Lobell، نويسنده , , Weikang Tao، نويسنده , , Vicki J. South، نويسنده , , Youwei Yan، نويسنده , , Lawrence C. Kuo، نويسنده , , Thomayant Prueksaritanont، نويسنده , , Donald E. Slaughter، نويسنده , , Cathy Shu، نويسنده , , et al.، نويسنده ,
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.
Keywords :
phenol , cancer , Phosphate prodrug , Dihydropyrrole , Kinesin , KSP , HERG , Antimitotic , Kinesin spindle protein
