Discovery
of Potent Benzolactam IRAK4 Inhibitors with
Robust in Vivo Activity
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
10.1021/acsmedchemlett.9b00380.s001
https://acs.figshare.com/articles/journal_contribution/Discovery_of_Potent_Benzolactam_IRAK4_Inhibitors_with_Robust_in_Vivo_Activity/10325036
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 <b>19</b> that
achieves robust in vivo inhibition of cytokines relevant to human
disease.
2019-11-18 22:16:25
IRAK 4.
TLR
blood assay
benzolactam IRAK 4 inhibitors
cytokine
Potent Benzolactam IRAK 4 Inhibitors
vivo inhibition
IL -1Rs
IRAK 4 inhibitors
molecule 19
disease-relevant pharmacodynamic models
Vivo Activity IRAK 4 kinase activity transduces
dihydrobenzofuran inhibitors