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).
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.
Kaplan
Joshua
J
Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, United States. kaplanj1@wyeth.com
Verheijen
Jeroen C
JC
Brooijmans
Natasja
N
Toral-Barza
Lourdes
L
Hollander
Irwin
I
Yu
Ker
K
Zask
Arie
A
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D003198:Computer Simulation; D055808:Drug Discovery; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D008958:Models, Molecular; D009025:Morpholines / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011714:Pyrans / Q000737:chemistry*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D011714:Pyrans; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; C118531:pyrazolopyridine; C476003:thienopyrimidine; C037574:morpholine; D000255:Adenosine Triphosphate; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases