Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation

William T. McElroy, Zheng Tan, Ginny Ho, Sunil Paliwal, Guoqing Li, W. Michael Seganish, Deen Tulshian, James Tata, Thierry O. Fischmann, Christopher Sondey, Hong Bian, Loretta Bober, James Jackson, Charles G. Garlisi, Kristine Devito, James Fossetta, Daniel Lundell, Xiaoda Niu

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

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).

Original languageEnglish
Pages (from-to)677-682
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume6
Issue number6
DOIs
StatePublished - 11 Jun 2015

Keywords

  • Interleukin-1 receptor-associated kinase 4
  • SAR
  • drug discovery
  • inflammation
  • structure-based drug design

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