PMID- 19894727
OWN - NLM
STAT- MEDLINE
DCOM- 20100106
LR  - 20211203
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 52
IP  - 24
DP  - 2009 Dec 24
TI  - 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.
PG  - 8010-24
LID - 10.1021/jm9013828 [doi]
AB  - 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).
FAU - Verheijen, Jeroen C
AU  - Verheijen JC
AD  - Wyeth Research, Pearl River, NY 10965, USA. verheij@wyeth.com
FAU - Richard, David J
AU  - Richard DJ
FAU - Curran, Kevin
AU  - Curran K
FAU - Kaplan, Joshua
AU  - Kaplan J
FAU - Lefever, Mark
AU  - Lefever M
FAU - Nowak, Pawel
AU  - Nowak P
FAU - Malwitz, David J
AU  - Malwitz DJ
FAU - Brooijmans, Natasja
AU  - Brooijmans N
FAU - Toral-Barza, Lourdes
AU  - Toral-Barza L
FAU - Zhang, Wei-Guo
AU  - Zhang WG
FAU - Lucas, Judy
AU  - Lucas J
FAU - Hollander, Irwin
AU  - Hollander I
FAU - Ayral-Kaloustian, Semiramis
AU  - Ayral-Kaloustian S
FAU - Mansour, Tarek S
AU  - Mansour TS
FAU - Yu, Ker
AU  - Yu K
FAU - Zask, Arie
AU  - Zask A
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Morpholines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyrimidines)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adenosine Triphosphate/*chemistry/metabolism
MH  - Binding, Competitive
MH  - Cell Growth Processes/drug effects
MH  - Cell Line, Tumor
MH  - Humans
MH  - Male
MH  - Models, Molecular
MH  - Morpholines/chemical synthesis/chemistry/pharmacology
MH  - Prostatic Neoplasms/drug therapy/pathology
MH  - Protein Kinase Inhibitors/chemical synthesis/chemistry/*pharmacology
MH  - Protein Kinases/*chemistry/metabolism
MH  - Pyrazoles/chemical synthesis/chemistry/pharmacology
MH  - Pyrimidines/chemical synthesis/chemistry/*pharmacology
MH  - Structure-Activity Relationship
MH  - TOR Serine-Threonine Kinases
EDAT- 2009/11/10 06:00
MHDA- 2010/01/07 06:00
CRDT- 2009/11/10 06:00
PHST- 2009/11/10 06:00 [entrez]
PHST- 2009/11/10 06:00 [pubmed]
PHST- 2010/01/07 06:00 [medline]
AID - 10.1021/jm9013828 [doi]
PST - ppublish
SO  - J Med Chem. 2009 Dec 24;52(24):8010-24. doi: 10.1021/jm9013828.