2-Arylureidophenyl-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)triazines as highly potent and selective ATP competitive mTOR inhibitors: optimization of human microsomal stability.
Isosteric replacement of one of the 3,5-ethylene-bridged morpholines in 2-arylureidophenyl-4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)triazines led to significant improvements in human microsomal stability. 3-R-Me-morpholine and tetrahydropyran were identified as preferred isosteres for the bridged morpholine. Combination of tetrahydropyran substitution with an N-Me-piperazinophenylureido group led to 27, that selectively suppressed mTOR biomarkers in vivo and possessed excellent efficacy in a murine xenograft model.
Verheijen
Jeroen C
JC
Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA. verheij@wyeth.com
Richard
David J
DJ
Curran
Kevin
K
Kaplan
Joshua
J
Yu
Ker
K
Zask
Arie
A
D000818:Animals; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008861:Microsomes / Q000187:drug effects* / Q000378:metabolism; D014183:Transplantation, Heterologous; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*
D014227:Triazines