Synthesis and SAR of 6-chloro-4-fluoroalkylamino-2-heteroaryl-5-(substituted)phenylpyrimidines as anti-cancer agents

The synthesis and SAR of a series of 6-chloro-4-fluoroalkylamino-2-heteroaryl-5-(substituted)phenylpyrimidines as anti-cancer agents are described. This series of 2-heteroarylpyrimidines was developed by modifying a series of anti-tumor [1,2,4]triazolo[1,5- a]pyrimidines and 2-cyanoaminopyrimidines...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2009, Vol.17 (1), p.111-118
Main Authors: Zhang, Nan, Ayral-Kaloustian, Semiramis, Nguyen, Thai, Hernandez, Richard, Lucas, Judy, Discafani, Carolyn, Beyer, Carl
Format: Article
Language:English
Subjects:
6-Chloro-4-fluoroalkylamino-2-heteroaryl-5-(substituted)phenylpyrimidines
Animals
Anti-cancer agents
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Proliferation - drug effects
General aspects
Humans
Medical sciences
Mice
Mice, Nude
Microtubule-stabilizing activity
Neoplasms - drug therapy
Pharmacology. Drug treatments
Pyrimidines - chemical synthesis
Pyrimidines - pharmacology
Structure-Activity Relationship
Tumor Burden - drug effects
Xenograft Model Antitumor Assays
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Summary:The synthesis and SAR of a series of 6-chloro-4-fluoroalkylamino-2-heteroaryl-5-(substituted)phenylpyrimidines as anti-cancer agents are described. This series of 2-heteroarylpyrimidines was developed by modifying a series of anti-tumor [1,2,4]triazolo[1,5- a]pyrimidines and 2-cyanoaminopyrimidines we reported earlier. For the 2-heteroaryl group, the best activity is obtained when the heteroaryl group has a nitrogen atom at the ortho-position to the pyrimidyl core. The structure–activity relationship for the rest of the molecule in this 2-heteroarylpyrimidine series mimics that of the [1,2,4]triazolo[1,5- a]pyrimidine series. Like triazolopyrimidines and 2-cyanoaminopyrimidines, the 2-heteroarylpyrimidines retain the capability to overcome multidrug resistance due to Pgp. Mechanism of action studies showed that the lead compounds behaved in the same manner as triazolopyrimidines and 2-cyanoaminopyrimidines. The lead compounds in this series are more potent than the corresponding triazolopyrimidines in vitro and in vivo. Compound 21 (PTI-868) showed tumor growth inhibition in several nude mouse xenograft models, and was selected to advance to preclinical development.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2008.11.016