Examining the Chirality, Conformation and Selective Kinase Inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (CP-690,550)

Here, we examine the significance that stereochemistry plays within the clinically relevant Janus kinase 3 (Jak3) inhibitor 1 (CP-690,550). A synthesis of all four enantiopure stereoisomers of the drug was carried out and an examination of each compound revealed that only the enantiopure 3R,4R isome...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2008-12, Vol.51 (24), p.8012-8018
Main Authors: Jiang, Jian-kang, Ghoreschi, Kamran, Deflorian, Francesca, Chen, Zhi, Perreira, Melissa, Pesu, Marko, Smith, Jeremy, Nguyen, Dac-Trung, Liu, Eric H, Leister, William, Costanzi, Stefano, O’Shea, John J, Thomas, Craig J
Format: Article
Language:English
Subjects:
Biological and medical sciences
Chemistry, Pharmaceutical - methods
Drug Design
Humans
Hydrogen Bonding
Immunomodulators
Inhibitory Concentration 50
Janus Kinase 2 - chemistry
Kinetics
Medical sciences
Models, Chemical
Models, Molecular
Molecular Conformation
Monte Carlo Method
Pharmacology. Drug treatments
Piperidines
Protein Binding
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - pharmacology
Pyrimidines - chemical synthesis
Pyrimidines - pharmacology
Pyrroles - chemical synthesis
Pyrroles - pharmacology
Stereoisomerism
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Summary:Here, we examine the significance that stereochemistry plays within the clinically relevant Janus kinase 3 (Jak3) inhibitor 1 (CP-690,550). A synthesis of all four enantiopure stereoisomers of the drug was carried out and an examination of each compound revealed that only the enantiopure 3R,4R isomer was capable of blocking Stat5 phosphorylation (Jak3 dependent). Each compound was profiled across a panel of over 350 kinases, which revealed a high level of selectivity for the Jak family kinases for these related compounds. Each stereoisomer retained a degree of binding to Jak3 and Jak2 and the 3R,4S and 3S,4R stereoisomers were further revealed to have binding affinity for selected members of the STE7 and STE20 subfamily of kinases. Finally, an appraisal of the minimum energy conformation of each stereoisomer and molecular docking at Jak3 was performed in an effort to better understand each compounds selectivity and potency profiles.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm801142b