TY - JOUR
T1 - Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation
AU - McElroy, William T.
AU - Tan, Zheng
AU - Ho, Ginny
AU - Paliwal, Sunil
AU - Li, Guoqing
AU - Seganish, W. Michael
AU - Tulshian, Deen
AU - Tata, James
AU - Fischmann, Thierry O.
AU - Sondey, Christopher
AU - Bian, Hong
AU - Bober, Loretta
AU - Jackson, James
AU - Garlisi, Charles G.
AU - Devito, Kristine
AU - Fossetta, James
AU - Lundell, Daniel
AU - Niu, Xiaoda
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/6/11
Y1 - 2015/6/11
N2 - IRAK4 is a critical upstream kinase in the IL-1R/TLR signaling pathway. Inhibition of IRAK4 is hypothesized to be beneficial in the treatment of autoimmune related disorders. A screening campaign identified a pyrazole class of IRAK4 inhibitors that were determined by X-ray crystallography to exhibit an unusual binding mode. SAR efforts focused on the identification of a potent and selective inhibitor with good aqueous solubility and rodent pharmacokinetics. Pyrazole C-3 piperidines were well tolerated, with N-sulfonyl analogues generally having good rodent oral exposure but poor solubility. N-Alkyl piperidines exhibited excellent solubility and reduced exposure. Pyrazoles possessing N-1 pyridine and fluorophenyl substituents were among the most active. Piperazine 32 was a potent enzyme inhibitor with good cellular activity. Compound 32 reduced the in vivo production of proinflammatory cytokines and was orally efficacious in a mouse antibody induced arthritis disease model of inflammation. (Chemical Equation Presented).
AB - IRAK4 is a critical upstream kinase in the IL-1R/TLR signaling pathway. Inhibition of IRAK4 is hypothesized to be beneficial in the treatment of autoimmune related disorders. A screening campaign identified a pyrazole class of IRAK4 inhibitors that were determined by X-ray crystallography to exhibit an unusual binding mode. SAR efforts focused on the identification of a potent and selective inhibitor with good aqueous solubility and rodent pharmacokinetics. Pyrazole C-3 piperidines were well tolerated, with N-sulfonyl analogues generally having good rodent oral exposure but poor solubility. N-Alkyl piperidines exhibited excellent solubility and reduced exposure. Pyrazoles possessing N-1 pyridine and fluorophenyl substituents were among the most active. Piperazine 32 was a potent enzyme inhibitor with good cellular activity. Compound 32 reduced the in vivo production of proinflammatory cytokines and was orally efficacious in a mouse antibody induced arthritis disease model of inflammation. (Chemical Equation Presented).
KW - Interleukin-1 receptor-associated kinase 4
KW - SAR
KW - drug discovery
KW - inflammation
KW - structure-based drug design
UR - https://www.scopus.com/pages/publications/84935898583
UR - https://www.scopus.com/pages/publications/84935898583#tab=citedBy
U2 - 10.1021/acsmedchemlett.5b00106
DO - 10.1021/acsmedchemlett.5b00106
M3 - Article
AN - SCOPUS:84935898583
VL - 6
SP - 677
EP - 682
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 6
ER -