title: 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.
abstract: 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.
authors.affiliation: Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA. verheij@wyeth.com
authors.forename: Jeroen C
authors.initials: JC
authors.lastname: Verheijen
authors.forename: David J
authors.initials: DJ
authors.lastname: Richard
authors.forename: Kevin
authors.initials: K
authors.lastname: Curran
authors.forename: Joshua
authors.initials: J
authors.lastname: Kaplan
authors.forename: Ker
authors.initials: K
authors.lastname: Yu
authors.forename: Arie
authors.initials: A
authors.lastname: Zask
mesh_terms: 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*
chemical_list: D014227:Triazines