Discovery and structure-activity relationship of 3-aminopyrid-2-ones as potent and selective interleukin-2 inducible T-cell kinase (Itk) inhibitors
| Autor: | Heather Twin, Adam Tanner, David Kay, Adam P. Curnock, Juan-Miguel Jimenez, Sharn Ramaya, Ronald Knegtel, Guy Brenchley, Shazia Keily, Andrew Miller, Jean-Damien Charrier, Steven Durrant, Philip N. Collier, Kieron Brown |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Pyridones Substrate Specificity Maleimides chemistry.chemical_compound Structure-Activity Relationship Adenosine Triphosphate Interleukin-2-Inducible T-Cell Kinase Catalytic Domain Drug Discovery Protein-Tyrosine Kinases Structure–activity relationship Protein Kinase Inhibitors biology Chemistry Kinase Active site Hydrogen Bonding Biochemistry Drug Design biology.protein Molecular Medicine Substrate specificity Selectivity Adenosine triphosphate |
| Zdroj: | Journal of medicinal chemistry. 54(7) |
| ISSN: | 1520-4804 |
| Popis: | Interleukin-2 inducible T-cell kinase (Itk) plays a role in T-cell functions, and its inhibition potentially represents an attractive intervention point to treat autoimmune and allergic diseases. Herein we describe the discovery of a series of potent and selective novel inhibitors of Itk. These inhibitors were identified by structure-based design, starting from a fragment generated de novo, the 3-aminopyrid-2-one motif. Functionalization of the 3-amino group enabled rapid enhancement of the inhibitory activity against Itk, while introduction of a substituted heteroaromatic ring in position 5 of the pyridone fragment was key to achieving optimal selectivity over related kinases. A careful analysis of the hydration patterns in the kinase active site was necessary to fully explain the observed selectivity profile. The best molecule prepared in this optimization campaign, 7v, inhibits Itk with a K(i) of 7 nM and has a good selectivity profile across kinases. |
| Databáze: | OpenAIRE |
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