title: Incorporation of water-solubilizing groups in pyrazolopyrimidine mTOR inhibitors: discovery of highly potent and selective analogs with improved human microsomal stability.
abstract: A series of highly potent and selective pyrazolopyrimidine mTOR inhibitors which contain water-solubilizing groups attached to the 6-arylureidophenyl moiety have been prepared. Such derivatives displayed superior potency to those in which these appendages were attached to alternative sites. In comparison to unfunctionalized arylureido compounds, these analogs demonstrated enhanced cellular potency and significantly improved stability towards human microsomes, resulting in an mTOR inhibitor with impressive efficacy in a xenograft model with an intermittent dosing regimen.
authors.affiliation: Chemical Sciences, Wyeth Research, 401 N. Middletown Rd, Pearl River, NY 10965, USA. richard4@wyeth.com
authors.forename: David J
authors.initials: DJ
authors.lastname: Richard
authors.forename: Jeroen C
authors.initials: JC
authors.lastname: Verheijen
authors.forename: Kevin
authors.initials: K
authors.lastname: Curran
authors.forename: Joshua
authors.initials: J
authors.lastname: Kaplan
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: Ker
authors.initials: K
authors.lastname: Yu
authors.forename: Arie
authors.initials: A
authors.lastname: Zask
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D055808:Drug Discovery; D004355:Drug Stability; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000201:enzymology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D012995:Solubility; D058570:TOR Serine-Threonine Kinases; D014867:Water / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D014867:Water; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases