Discovery and hit-to-lead optimization of 2,6-diaminopyrimidine inhibitors of interleukin-1 receptor-associated kinase 4
| Autor: | Xiaoda Niu, W. Michael Seganish, R. Jason Herr, James P. Harding, Deen Tulshian, Larry Yet, Brian J. Lavey, Thierry O. Fischmann, Koraboina Chandra Prakash, Christopher Sondey, William J. Greenlee, Jinhai Yang, Venukrishnan Komanduri, William T. McElroy |
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| Rok vydání: | 2015 |
| Předmět: |
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Molecular Stereochemistry Clinical Biochemistry Pharmaceutical Science Biochemistry Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Humans Protein Kinase Inhibitors Molecular Biology Ligand efficiency Dose-Response Relationship Drug Molecular Structure Chemistry Drug discovery Organic Chemistry Interleukin Hit to lead Ligand (biochemistry) IRAK4 Interleukin-1 Receptor-Associated Kinases Pyrimidines Diaminopyrimidine Molecular Medicine Signal transduction |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 25:1836-1841 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2015.03.043 |
| Popis: | Interleukin receptor-associated kinase 4 (IRAK4) is a critical element of the Toll-like/interleukin-1 receptor inflammation signaling pathway. A screening campaign identified a novel diaminopyrimidine hit that exhibits weak IRAK4 inhibitory activity and a ligand efficiency of 0.25. Hit-to-lead activities were conducted through independent SAR studies of each of the four pyrimidine substituents. Optimal activity was observed upon removal of the pyrimidine C-4 chloro substituent. The intact C-6 carboribose is required for IRAK4 inhibition. Numerous heteroaryls were tolerated at the C-5 position, with azabenzothiazoles conferring the best activities. Aminoheteroaryls were preferred at the C-2 position. These studies led to the discovery of inhibitors 35, 36, and 38 that exhibit nanomolar inhibition of IRAK4, improved ligand efficiencies, and modest kinase selectivities. |
| Databáze: | OpenAIRE |
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