title: Pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimization of the 1-substituent.
abstract: A series of pyrazolopyrimidine mammalian Target Of Rapamycin (mTOR) inhibitors with various substituents at the 1-position have been prepared, resulting in compounds with excellent potency, selectivity and microsomal stability. Combination of a 1-cyclohexyl ketal group with a 2,6-ethylene bridged morpholine in the 4-position and a ureidophenyl group in the 6-positon resulted in compound 8a, that selectively suppressed key mTOR biomarkers in vivo for at least 8h following iv administration and showed excellent oral activity in a xenograft tumor model.
authors.affiliation: Chemical Sciences, Wyeth Research, 401 N. Middletown Rd, Pearl River, NY 10965, USA. currank@wyeth.com
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Curran
authors.forename: Jeroen C
authors.initials: JC
authors.lastname: Verheijen
authors.forename: Joshua
authors.initials: J
authors.lastname: Kaplan
authors.forename: David J
authors.initials: DJ
authors.lastname: Richard
authors.forename: Lourdes
authors.initials: L
authors.lastname: Toral-Barza
authors.forename: Irwin
authors.initials: I
authors.lastname: Hollander
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
authors.forename: Ker
authors.initials: K
authors.lastname: Yu
authors.forename: Arie
authors.initials: A
authors.lastname: Zask
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D004355:Drug Stability; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008861:Microsomes / Q000201:enzymology; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases; D023041:Xenograft Model Antitumor Assays
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine; D000255:Adenosine Triphosphate; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases