title: Discovery of 4-morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as highly potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimization of the 6-aryl substituent.
abstract: Design and synthesis of a series of 4-morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as potent and selective inhibitors of the mammalian target of rapamycin (mTOR) are described. Optimization of the 6-aryl substituent led to the discovery of inhibitors carrying 6-ureidophenyl groups, the first reported active site inhibitors of mTOR with subnanomolar inhibitory concentrations. The data presented in this paper show that 6-arylureidophenyl substituents led to potent mixed inhibitors of mTOR and phosphatidylinositol 3-kinase alpha (PI3K-alpha), whereas 6-alkylureidophenyl appendages gave highly selective mTOR inhibitors. Combination of 6-alkylureidophenyl groups with 1-carbamoylpiperidine substitution resulted in compounds with subnanomolar IC(50) against mTOR and greater than 1000-fold selectivity over PI3K-alpha. In addition, structure based drug design resulted in the preparation of several 6-arylureidophenyl-1H-pyrazolo[3,4-d]pyrimidines, substituted in the 4-position of the arylureido moiety with water solubilizing groups. These compounds combined potent mTOR inhibition (IC(50) < 1 nM) with unprecedented activity in cellular proliferation assays (IC(50) < 1 nM).
authors.affiliation: 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: Mark
authors.initials: M
authors.lastname: Lefever
authors.forename: Pawel
authors.initials: P
authors.lastname: Nowak
authors.forename: David J
authors.initials: DJ
authors.lastname: Malwitz
authors.forename: Natasja
authors.initials: N
authors.lastname: Brooijmans
authors.forename: Lourdes
authors.initials: L
authors.lastname: Toral-Barza
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Zhang
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.forename: Irwin
authors.initials: I
authors.lastname: Hollander
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
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; D001667:Binding, Competitive; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases
chemical_list: D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D000255:Adenosine Triphosphate; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases