Addressing PXR liabilities of phthalazine-based hedgehog/smoothened antagonists using novel pyridopyridazines

Pyridopyridazine antagonists of the hedgehog signaling pathway are described. Designed to optimize our previously described phthalazine smoothened antagonists, a representative compound, 27, eliminates a PXR liability while retaining potency and in vitro metabolic stability. Moreover, the compound h...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-08, Vol.20 (15), p.4607-4610
Main Authors: Kaizerman, Jacob A., Aaron, Wade, An, Songzhu, Austin, Richard, Brown, Matt, Chong, Angela, Huang, Tom, Hungate, Randall, Jiang, Ben, Johnson, Michael G., Lee, Gary, Lucas, Brian S., Orf, Jessica, Rong, Minqing, Toteva, Maria M., Wickramasinghe, Dineli, Xu, Guifen, Ye, Qiuping, Zhong, Wendy, McMinn, Dustin L.
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Biological and medical sciences
Cancer
General aspects
Hedgehog
Hedgehog Proteins - antagonists & inhibitors
Hedgehog Proteins - metabolism
Humans
Medical sciences
Mice
Microsomes, Liver - metabolism
Oncology
Pharmacology. Drug treatments
Phthalazines - chemical synthesis
Phthalazines - chemistry
Phthalazines - pharmacokinetics
Piperazines - chemical synthesis
Piperazines - chemistry
Piperazines - pharmacokinetics
Pyridazines - chemical synthesis
Pyridazines - chemistry
Pyridazines - pharmacokinetics
Rats
Receptors, G-Protein-Coupled - antagonists & inhibitors
Receptors, G-Protein-Coupled - metabolism
Receptors, Steroid - chemistry
Receptors, Steroid - metabolism
Signal Transduction
SMO
Smoothened
Smoothened Receptor
Structure-Activity Relationship
Tylosin - analogs & derivatives
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Description
Summary:Pyridopyridazine antagonists of the hedgehog signaling pathway are described. Designed to optimize our previously described phthalazine smoothened antagonists, a representative compound, 27, 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. 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.06.006