Open AccessDiscovery of Potent Benzolactam IRAK4 Inhibitors with Robust in Vivo Activity
Author(s) -
Naomi S. Rajapaksa,
Alberto Gobbi,
Joy Drobnick,
Steven Do,
Aleksandr Kolesnikov,
Jun Liang,
Yongsheng Chen,
Swathi Sujatha-Bhaskar,
Zhiyu Huang,
Hans D. Brightbill,
Ross Francis,
Christine Yu,
Edna F. Choo,
Kevin DeMent,
Yingqing Ran,
Lê Văn An,
Claire Emson,
Jonathan Maher,
John S. Wai,
Brent McKenzie,
P.J. Lupardus,
Ali A. Zarrin,
James R. Kiefer,
Marian C. Bryan
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00380
Subject(s) - in vivo , chemokine , computational biology , drug discovery , human disease , pharmacology , disease , biology , bioinformatics , medicine , inflammation , immunology , microbiology and biotechnology , pathology
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.