Discovery of 2-pyrimidyl-5-amidothiophenes as potent inhibitors for AKT: Synthesis and SAR studies

A series of 2-pyrimidyl-5-amidothiophenes has been synthesized and evaluated for AKT inhibition. Compound 2aa is a potent AKT inhibitor and showed cellular activity including antiproliferation and downstream target modulation. Selectivity profile is described. A co-crystal of 2aa with PKA is determi...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2006-08, Vol.16 (16), p.4163-4168
Main Authors: Lin, Xiaodong, Murray, Jeremy M., Rico, Alice C., Wang, Michael X., Chu, Daniel T., Zhou, Yasheen, Rosario, Merci Del, Kaufman, Susan, Ma, Sylvia, Fang, Eric, Crawford, Kenneth, Jefferson, A.B.
Format: Article
Language:English
Subjects:
Biological and medical sciences
Cancer
Cell Line, Tumor
Cell Proliferation
Chemistry, Pharmaceutical - methods
Crystallization
Crystallography, X-Ray
Enzyme Inhibitors - pharmacology
Humans
Inhibitory Concentration 50
kinase inhibitor
Medical sciences
Miscellaneous
Models, Chemical
Models, Molecular
Pharmacology. Drug treatments
Protein Binding
Protein kinase B/AKT
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Structure-Activity Relationship
Substituted pyrimidine
Thiophenes - chemical synthesis
Thiophenes - chemistry
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Summary:A series of 2-pyrimidyl-5-amidothiophenes has been synthesized and evaluated for AKT inhibition. Compound 2aa is a potent AKT inhibitor and showed cellular activity including antiproliferation and downstream target modulation. Selectivity profile is described. A co-crystal of 2aa with PKA is determined and discussed. A series of 2-pyrimidyl-5-amidothiophenes has been synthesized and evaluated for AKT inhibition. SAR studies resulted in potent inhibitors of AKT with IC 50 values as low as single digit nanomolar as represented by compound 2aa. Compound 2aa showed cellular activity including antiproliferation and downstream target modulation. Selectivity profile is described. A co-crystal of 2aa with PKA is determined and discussed.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2006.05.092