The imidazo[1,2-a]pyridine ring system as a scaffold for potent dual phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors

[Display omitted] Based on lead compound 1, which was discovered from a high-throughput screen, a series of PI3Kα/mTOR inhibitors were evaluated that contained an imidazo[1,2-a]pyridine as a core replacement for the benzimidazole contained in 1. By exploring various ring systems that occupy the affi...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2015-10, Vol.25 (19), p.4136-4142
Hauptverfasser:	Stec, Markian M., Andrews, Kristin L., Bo, Yunxin, Caenepeel, Sean, Liao, Hongyu, McCarter, John, Mullady, Erin L., San Miguel, Tisha, Subramanian, Raju, Tamayo, Nuria, Whittington, Douglas A., Wang, Ling, Wu, Tian, Zalameda, Leeanne P., Zhang, Nancy, Hughes, Paul E., Norman, Mark H.
Format:	Artikel
Sprache:	eng
Schlagworte:	Affinity pocket Animals Crystallography, X-Ray Dose-Response Relationship, Drug Humans Imidazo[1,2-a]pyridine Kinase inhibitor Mice Microsomes, Liver - chemistry Microsomes, Liver - metabolism Models, Molecular Molecular Structure mTOR Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - metabolism Phosphoinositide 3-kinase Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Pyridines - chemistry Rats Ribose pocket Structure-Activity Relationship TOR Serine-Threonine Kinases - antagonists & inhibitors TOR Serine-Threonine Kinases - metabolism
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Zusammenfassung:	[Display omitted] Based on lead compound 1, which was discovered from a high-throughput screen, a series of PI3Kα/mTOR inhibitors were evaluated that contained an imidazo[1,2-a]pyridine as a core replacement for the benzimidazole contained in 1. By exploring various ring systems that occupy the affinity pocket, two fragments containing a methoxypyridine were identified that gave
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2015.08.016