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.
Zask
Arie
A
Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA. ariez@aol.com
Verheijen
Jeroen C
JC
Richard
David J
DJ
Kaplan
Joshua
J
Curran
Kevin
K
Toral-Barza
Lourdes
L
Lucas
Judy
J
Hollander
Irwin
I
Yu
Ker
K
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