9H-Carbazole-1-carboxamides as potent and selective JAK2 inhibitors

The discovery, synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selective ATP-competitive inhibitors of Janus kinase 2 (JAK2) are discussed. [Display omitted] The discovery, synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selective ATP-competi...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2015-07, Vol.25 (14), p.2809-2812
Hauptverfasser:	Zimmermann, Kurt, Sang, Xiaopeng, Mastalerz, Harold A., Johnson, Walter L., Zhang, Guifen, Liu, Qingjie, Batt, Douglas, Lombardo, Louis J., Vyas, Dinesh, Trainor, George L., Tokarski, John S., Lorenzi, Matthew V., You, Dan, Gottardis, Marco M., Lippy, Jonathan, Khan, Javed, Sack, John S., Purandare, Ashok V.
Format:	Artikel
Sprache:	eng
Schlagworte:	Amides - chemistry Amides - metabolism Amides - pharmacology Binding Sites Carbazoles - chemistry Cell Line, Tumor Cell Proliferation - drug effects Crystallography, X-Ray Humans JAK JAK family selectivity JAK1 JAK2 JAK3 Janus Kinase 1 - antagonists & inhibitors Janus Kinase 1 - metabolism Janus Kinase 2 - antagonists & inhibitors Janus Kinase 2 - metabolism Janus Kinase 3 - antagonists & inhibitors Janus Kinase 3 - metabolism Molecular Dynamics Simulation Myeloproliferative disorders Myeloproliferative neoplasms Protein Binding Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - metabolism Protein Kinase Inhibitors - pharmacology Protein Structure, Tertiary Structure-Activity Relationship TYK2
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Zusammenfassung:	The discovery, synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selective ATP-competitive inhibitors of Janus kinase 2 (JAK2) are discussed. [Display omitted] The discovery, synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selective ATP-competitive inhibitors of Janus kinase 2 (JAK2) are discussed. Optimization for JAK family selectivity led to compounds 14 and 21, with greater than 45-fold selectivity for JAK2 over all other members of the JAK kinase family.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2015.04.101