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Addressing PXR liabilities of phthalazine-based hedgehog/smoothened antagonists using novel pyridopyridazines
Jacob A Kaizerman1, Wade Aaron, Songzhu An
1Amgen, Inc., South San Francisco, CA 94080, USA.
Bioorganic & Medicinal Chemistry Letters
|July 3, 2010
Abstract:
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.