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.
MeSH terms
-
Animals
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / chemistry*
-
Antineoplastic Agents / pharmacokinetics
-
Cell Line, Tumor
-
Drug Discovery
-
Drug Stability
-
Humans
-
Intracellular Signaling Peptides and Proteins / drug effects*
-
Mice
-
Mice, Nude
-
Microsomes, Liver / enzymology*
-
Phosphoinositide-3 Kinase Inhibitors*
-
Protein Kinase Inhibitors / chemical synthesis
-
Protein Kinase Inhibitors / chemistry*
-
Protein Kinase Inhibitors / pharmacokinetics
-
Protein Serine-Threonine Kinases / drug effects*
-
Pyrazoles / chemical synthesis
-
Pyrazoles / chemistry*
-
Pyrazoles / pharmacokinetics
-
Pyrimidines / chemical synthesis
-
Pyrimidines / chemistry*
-
Pyrimidines / pharmacokinetics
-
Solubility
-
TOR Serine-Threonine Kinases
-
Water / chemistry
-
Xenograft Model Antitumor Assays
Substances
-
Antineoplastic Agents
-
Intracellular Signaling Peptides and Proteins
-
Phosphoinositide-3 Kinase Inhibitors
-
Protein Kinase Inhibitors
-
Pyrazoles
-
Pyrimidines
-
Water
-
MTOR protein, human
-
mTOR protein, mouse
-
Protein Serine-Threonine Kinases
-
TOR Serine-Threonine Kinases