Discovery of Potent Benzolactam IRAK4 Inhibitors with Robust in Vivo Activity
| Autor: | Zhiyu Huang, Yingqing Ran, Le An, Alberto Gobbi, Jonathan Maher, Claire Emson, Naomi S. Rajapaksa, Edna F. Choo, Yongsheng Chen, Steven Do, Aleksandr Kolesnikov, Ali A. Zarrin, Christine Yu, Marian C. Bryan, Joy Drobnick, Swathi Sujatha-Bhaskar, Hans Brightbill, James R. Kiefer, Jun Liang, Brent S. McKenzie, Ross Francis, John S. Wai, Patrick J. Lupardus, Kevin DeMent |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Chemokine
Systemic lupus erythematosus High interest biology 010405 organic chemistry business.industry Organic Chemistry Pharmacology IRAK4 medicine.disease 01 natural sciences Biochemistry Pyrazolopyrimidine 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry.chemical_compound chemistry In vivo Drug Discovery biology.protein Medicine Kinase activity business Whole blood |
| Zdroj: | ACS Med Chem Lett |
| Popis: | [Image: see text] IRAK4 kinase activity transduces signaling from multiple IL-1Rs and TLRs to regulate cytokines and chemokines implicated in inflammatory diseases. As such, there is high interest in identifying selective IRAK4 inhibitors for the treatment of these disorders. We previously reported the discovery of potent and selective dihydrobenzofuran inhibitors of IRAK4. Subsequent studies, however, showed inconsistent inhibition in disease-relevant pharmacodynamic models. Herein, we describe application of a human whole blood assay to the discovery of a series of benzolactam IRAK4 inhibitors. We identified potent molecule 19 that achieves robust in vivo inhibition of cytokines relevant to human disease. |
| Databáze: | OpenAIRE |
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