Discovery of Potent Benzolactam IRAK4 Inhibitors with Robust in Vivo Activity
Year: 2019
Type: article
Abstract: 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.
Source: ACS Medicinal Chemistry Letters
Authors: Naomi S. Rajapaksa, Alberto Gobbi, Joy Drobnick, Steven Do, Aleksandr Kolesnikov, Jun Liang, Yongsheng Chen, Swathi Sujatha-Bhaskar, Zhiyu Huang, Hans Brightbill, Ross Francis, Christine Yu, Edna F. Choo, Kevin DeMent, Yingqing Ran, Le An, Claire Emson, Jonathan Maher, John Wai, Brent S. McKenzie, Patrick J. Lupardus, Ali A. Zarrin, James R. Kiefer, Marian C. Bryan
Institutions: Genentech, WuXi AppTec (China)
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2988876253