Discovery of 2-ureidophenyltriazines bearing bridged morpholines as potent and selective ATP-competitive mTOR inhibitors.
Incorporation of bridged morpholines in monocyclic triazine PI3K/mTOR inhibitors gave compounds with increased mTOR selectivity relative to the corresponding morpholine analogs. Compounds with ureidophenyl groups gave highly potent and selective mTOR inhibitors. Potency and selectivity was demonstrated both in vitro and in vivo through biomarker suppression studies. Select compounds exhibited potent inhibition of tumor growth in nude mouse xenograft assays upon PO and IV administration.
Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA. ariez@aol.com
Arie
A
Zask
Jeroen C
JC
Verheijen
David J
DJ
Richard
Joshua
J
Kaplan
Kevin
K
Curran
Lourdes
L
Toral-Barza
Judy
J
Lucas
Irwin
I
Hollander
Ker
K
Yu
D000255:Adenosine Triphosphate / Q000737:chemistry*; D000818:Animals; D055808:Drug Discovery; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D058570:TOR Serine-Threonine Kinases; D014227:Triazines / Q000737:chemistry* / Q000494:pharmacology*
D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D014227:Triazines; D000255:Adenosine Triphosphate; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases