The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: Lead optimization
| Autor: | Lin Xu, Grace Chan, Melaney Bouthillette, Craig Rosenstein, Sathyajith E. Kumarasinghe, C. Gary Marshall, Tony Siu, Anjili Mathur, Alan B. Northrup, Michael D. Altman, Christopher J. Dinsmore, Matthew H. Katcher, Catherine White, Eric Bachman, Jonathan R. Young |
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| Rok vydání: | 2014 |
| Předmět: |
Molecular model
Pyridones Stereochemistry Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science Molecular Dynamics Simulation Biochemistry Structure-Activity Relationship Adenosine Triphosphate In vivo Drug Discovery Animals Potency Protein Kinase Inhibitors Molecular Biology chemistry.chemical_classification Sulfonamides Binding Sites Janus kinase 2 biology Chemistry Kinase Organic Chemistry Janus Kinase 2 Protein Structure Tertiary Rats Lipophilicity biology.protein Molecular Medicine Selectivity Half-Life Tricyclic |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 24:1466-1471 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2014.02.011 |
| Popis: | This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor–water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity. |
| Databáze: | OpenAIRE |
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