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

Journal Article · · ACS Medicinal Chemistry Letters
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  1. Merck Research Lab., Kenilworth, NJ (United States)
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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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
OSTI ID:
1404972
Journal Information:
ACS Medicinal Chemistry Letters, Vol. 6, Issue 6; ISSN 1948-5875
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 36 works
Citation information provided by
Web of Science

References (22)

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Cited By (11)

Safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06650833, a selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, in single and multiple ascending dose randomized phase 1 studies in healthy subjects journal December 2019
Design of a Novel and Selective IRAK4 Inhibitor Using Topological Water Network Analysis and Molecular Modeling Approaches journal November 2018
Kinase inhibitors: the road ahead journal March 2018
Selective interleukin-1 receptor–associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy journal November 2015
Dimethyl Fumarate Disrupts Human Innate Immune Signaling by Targeting the IRAK4–MyD88 Complex journal March 2019
Recent Progress in the Molecular Recognition and Therapeutic Importance of Interleukin-1 Receptor-Associated Kinase 4 journal November 2016
Safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06650833, a selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, in single and multiple ascending dose randomized phase 1 studies in healthy subjects journal December 2019
Identification of Toll-like receptor signaling inhibitors based on selective activation of hierarchically acting signaling proteins journal August 2018
IRAK4 inhibition to shut down TLR signaling in autoimmunity and MyD88-dependent lymphomas journal December 2015
Inhibition of interleukin-1 receptor-associated kinase 1 (IRAK1) as a therapeutic strategy journal September 2018
Conformational flexibility and inhibitor binding to unphosphorylated interleukin-1 receptor–associated kinase 4 (IRAK4) journal January 2019

Figures / Tables (6)

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