Title of article :
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
Author/Authors :
Christopher D. Cox، نويسنده , , Maricel Torrent، نويسنده , , Michael J. Breslin، نويسنده , , Brenda J. Mariano، نويسنده , , David B. Whitman، نويسنده , , Paul J. Coleman، نويسنده , , Carolyn A. Buser، نويسنده , , Eileen S. Walsh، نويسنده , , Kelly Hamilton، نويسنده , , Michael D. Schaber، نويسنده , , Robert B. Lobell، نويسنده , , Weikang Tao، نويسنده , , Vicki J. South، نويسنده , , Nancy E. Kohl، نويسنده , , Youwei Yan، نويسنده , , Lawrence C. Kuo، نويسنده , , Thomayant Prueksaritanont، نويسنده , , Donald E. Slaughter، نويسنده , , Chunze Li، نويسنده , , Elizabeth Mahan، نويسنده , , et al.، نويسنده ,
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.
Keywords :
structure-based design , Dihydropyrazole , Anti-mitotic agents , Kinesin spindle protein
