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Bilodeau MT, Balitza AE, Koester TJ, Manley PJ, Rodman LD, Buser-Doepner C, Coll KE, Fernandes C, Gibbs JB, Heimbrook DC, Huckle WR, Kohl N, Lynch JJ, Mao X, McFall RC, McLoughlin D, Miller-Stein CM, Rickert KW, Sepp-Lorenzino L, Shipman JM, Subramanian R, Thomas KA, Wong BK, Yu S, Hartman GD: Potent N-(1,3-thiazol-2-yl) pyridin-2-amine vascular endothelial growth factor receptor tyrosine kinase inhibitors with excellent pharmacokinetics and low affinity for the hERG ion channel. J Med Chem. 2004 Dec 2;47(25):6363-72.
A series of N-(1,3-thiazol-2-yl) pyridin-2-amine KDR kinase inhibitors have been developed that possess optimal properties. Compounds have been discovered that exhibit excellent in vivo potency. The particular challenges of overcoming hERG binding activity and QTc increases in vivo in addition to achieving good pharmacokinetics have been acomplished by discovering a unique class of amine substituents. These compounds have a favorable kinase selectivity profile that can be accentuated with appropriate substitution. |
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