- Addressing PXR liabilities of phthalazine-based hedgehog/smoothened antagonists using novel pyridopyridazines.
Addressing PXR liabilities of phthalazine-based hedgehog/smoothened antagonists using novel pyridopyridazines.
Bioorganic & medicinal chemistry letters (2010-07-03)
Jacob A Kaizerman, Wade Aaron, Songzhu An, Richard Austin, Matt Brown, Angela Chong, Tom Huang, Randall Hungate, Ben Jiang, Michael G Johnson, Gary Lee, Brian S Lucas, Jessica Orf, Minqing Rong, Maria M Toteva, Dineli Wickramasinghe, Guifen Xu, Qiuping Ye, Wendy Zhong, Dustin L McMinn
PMID20594845
RESUMEN
Pyridopyridazine antagonists of the hedgehog signaling pathway are described. Designed to optimize our previously described phthalazine smoothened antagonists, a representative compound eliminates a PXR liability while retaining potency and in vitro metabolic stability. Moreover, the compound has improved efficacy in a hedgehog/smoothened signaling mouse pharmacodynamic model.