Discovery of 3,6-dihydro-2H-pyran as a morpholine replacement in 6-aryl-1H-pyrazolo[3,4-d]pyrimidines and 2-arylthieno[3,2-d]pyrimidines: ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR)

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 2; pp. 640 - 643
• Main Authors: KAPLAN, Joshua, VERHEIJEN, Jeroen C, BROOIJMANS, Natasja, TORAL-BARZA, Lourdes, HOLLANDER, Irwin, YU, Ker, ZASK, Arie
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 15-01-2010
• Subjects: Adenosine Triphosphate - chemistry; Adenosine Triphosphate - metabolism; Animals; Antineoplastic agents; Binding Sites; Binding, Competitive; Biological and medical sciences; Computer Simulation; Drug Discovery; General aspects; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - metabolism; Medical sciences; Mice; Microsomes - metabolism; Models, Molecular; Morpholines - chemistry; Pharmacology. Drug treatments; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Pyrans - chemistry; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; TOR Serine-Threonine Kinases; Enzyme; Transferases; Non-specific serine/threonine protein kinase; Pyran derivatives; Competitive inhibition; In vitro; Modeling; Biological activity; 1-Phosphatidylinositol 3-kinase; Pyridine derivatives; Signal transduction; Pyrazolopyrimidine derivatives; Molecular model; Mammalian target of rapamycin; Ureas; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.11.050

The morpholine hinge-region binding group on a series of pyrazolopyrimidine and thienopyrimidine mammalian target of rapamycin (mTOR) inhibitors was replaced with 3,6-dihydro-2H-pyran (DHP), giving compounds of equivalent potency and selectivity versus PI3K. These results establish the DHP group as a hinge-region binding motif for the preparation of highly potent and selective mTOR inhibitors.