Abstract
High throughput screening to identify inhibitors of the mTOR kinase revealed sulfonyl-morpholino-pyrimidine 1 as an attractive start point. The compound displayed good physicochemical properties and selectivity over related kinases such as PI3Kα. Library preparation of related analogs allowed the establishment of additional SAR understanding and in particular the requirement for a key hydrogen bond donor motif at the 4-position of the phenyl ring in compounds such as indole 19. Isosteric replacement of the indole functionality led to the identification of urea compounds such as 32 that show good levels of mTOR inhibition in both enzyme and cellular assays.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
-
Animals
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / pharmacology
-
Biological Availability
-
Cell Line, Tumor
-
Humans
-
Hydrogen Bonding
-
Indoles / chemistry
-
Inhibitory Concentration 50
-
Morpholines / chemical synthesis*
-
Morpholines / pharmacology
-
Phosphatidylinositol 3-Kinases / metabolism
-
Protein Kinase Inhibitors / chemical synthesis*
-
Protein Kinase Inhibitors / pharmacology
-
Pyrimidines / chemical synthesis*
-
Pyrimidines / pharmacology
-
Rats
-
Structure-Activity Relationship
-
Sulfones / chemical synthesis*
-
Sulfones / pharmacology
-
TOR Serine-Threonine Kinases / antagonists & inhibitors*
-
TOR Serine-Threonine Kinases / chemistry
-
Urea / analogs & derivatives
-
Urea / chemistry
Substances
-
Antineoplastic Agents
-
Indoles
-
Morpholines
-
Protein Kinase Inhibitors
-
Pyrimidines
-
Sulfones
-
Urea
-
MTOR protein, human
-
TOR Serine-Threonine Kinases