Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors
| Autor: | Eileen S. Walsh, Steve Stirdivant, George D. Hartman, Kelly Hamilton, Marc Abrams, Robert M. Garbaccio, Laura Sepp-Lorenzino, Lawrence Kuo, Steve Beck, Joan Zugay Murphy, Constantine Kreatsoulas, Justin T. Steen, Sanjeev Munshi, Carolyn A. Buser, Weikang Tao, Shaei Huang, Youwei Yan, V V Sardana, Bob Drakas, Mari Ikuta, James Hardwick, Keith W. Rickert, Mark E. Fraley, Elizabeth Mahan, Xianzhi Mao, Rob Lobell, Michael Reilly |
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| Rok vydání: | 2006 |
| Předmět: |
Indoles
Stereochemistry Clinical Biochemistry Pharmaceutical Science Quinolones Crystallography X-Ray Biochemistry Polar surface area Structure-Activity Relationship Drug Discovery Animals Humans Structure–activity relationship Potency Enzyme Inhibitors Binding site Molecular Biology Cell potency chemistry.chemical_classification Binding Sites biology Organic Chemistry Active site Enzyme chemistry Enzyme inhibitor Drug Design Checkpoint Kinase 1 biology.protein Molecular Medicine Hydrophobic and Hydrophilic Interactions Protein Kinases |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 16:5907-5912 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2006.08.053 |
| Popis: | Through a comparison of X-ray co-crystallographic data for 1 and 2 in the Chek1 active site, it was hypothesized that the affinity of the indolylquinolinone series (2) for Chek1 kinase would be improved via C6 substitution into the hydrophobic region I (HI) pocket. An efficient route to 6-bromo-3-indolyl-quinolinone (9) was developed, and this series was rapidly optimized for potency by modification at C6. A general trend was observed among these low nanomolar Chek1 inhibitors that compounds with multiple basic amines, or elevated polar surface area (PSA) exhibited poor cell potency. Minimization of these parameters (basic amines, PSA) resulted in Chek1 inhibitors with improved cell potency, and preliminary pharmacokinetic data are presented for several of these compounds. |
| Databáze: | OpenAIRE |
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