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...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-08, Vol.20 (15), p.4607-4610
Hauptverfasser:	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:	Artikel
Sprache:	eng
Schlagworte:	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
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	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