Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

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

Journal Article · · ACS Medicinal Chemistry Letters
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1]
  1. Merck Research Lab., Kenilworth, NJ (United States)
+ Show Author Affiliations

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 (US)
Sponsoring Organization:
USDOE Office of Science (SC)
OSTI ID:
1404972
Journal Information:
ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 6 Vol. 6; ISSN 1948-5875
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (22)

Animal models of rheumatoid arthritis: FORUM journal August 2009
Cassette-accelerated rapid rat screen: a systematic procedure for the dosing and liquid chromatography/atmospheric pressure ionization tandem mass spectrometric analysis of new chemical entities as part of new drug discovery journal January 2001
Epidemiology and Estimated Population Burden of Selected Autoimmune Diseases in the United States journal September 1997
The potential of targeting Toll-like receptor 2 in autoimmune and inflammatory diseases journal November 2007
Advances in the Discovery of Small-Molecule IRAK4 Inhibitors book January 2014
Identification and optimization of indolo[2,3-c]quinoline inhibitors of IRAK4 journal May 2014
Inflammation, ageing and chronic disease journal August 2014
The impact of aromatic ring count on compound developability – are too many aromatic rings a liability in drug design? journal November 2009
IRAK-4 – a shared NF-κB activator in innate and acquired immunity journal December 2006
Recent Advances in the Discovery of Small Molecule Inhibitors of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as a Therapeutic Target for Inflammation and Oncology Disorders: Miniperspective journal July 2014
The problem of choice: current biologic agents and future prospects in RA journal February 2013
Targeting Toll-like receptors with small molecule agents journal January 2013
IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase journal April 2002
A Clean and Rapid Synthesis of 5-Amino and 5-Alkoxycarbonylpyrazoles Using Montomorillonite Under acid free Conditions journal October 2004
Utility of unbound plasma drug levels and P-glycoprotein transport data in prediction of central nervous system exposure journal May 2009
Inflammation and cardiovascular disease mechanisms journal February 2006
Jakpot! New small molecules in autoimmune and inflammatory diseases journal December 2013
The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress journal December 2008
Pyogenic Bacterial Infections in Humans with IRAK-4 Deficiency journal March 2003
Cancer and Inflammation: An Old Intuition with Rapidly Evolving New Concepts journal April 2012
A Novel Benzenediamine Derivate Rescued Mice from Experimental Sepsis by Attenuating Proinflammatory Mediators via IRAK4 journal August 2014
The Structure-Based Design of ATP-Site Directed Protein Kinase Inhibitors journal September 1999

Cited By (11)

IRAK4 inhibition to shut down TLR signaling in autoimmunity and MyD88-dependent lymphomas journal December 2015
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
Inhibition of interleukin-1 receptor-associated kinase 1 (IRAK1) as a therapeutic strategy journal September 2018
Recent Progress in the Molecular Recognition and Therapeutic Importance of Interleukin-1 Receptor-Associated Kinase 4 journal November 2016
Kinase inhibitors: the road ahead journal March 2018
Review: biologically active pyrazole derivatives journal January 2017
Conformational flexibility and inhibitor binding to unphosphorylated interleukin-1 receptor–associated kinase 4 (IRAK4) journal January 2019
Selective interleukin-1 receptor–associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy journal November 2015
Identification of Toll-like receptor signaling inhibitors based on selective activation of hierarchically acting signaling proteins journal August 2018
Design of a Novel and Selective IRAK4 Inhibitor Using Topological Water Network Analysis and Molecular Modeling Approaches journal November 2018
Dimethyl Fumarate Disrupts Human Innate Immune Signaling by Targeting the IRAK4–MyD88 Complex journal March 2019

Figures / Tables (6)

Figure 1(p. 2)figure Figure 1
Scheme 1(p. 2)figure Scheme 1
Table 1(p. 3)table Table 1
Table 2(p. 4)table Table 2
Figure 2(p. 5)figure Figure 2
Figure 3(p. 5)figure Figure 3

Similar Records

Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation
Journal Article · Thu Jun 01 00:00:00 EDT 2017 · Bioorganic and Medicinal Chemistry Letters · OSTI ID:1404982
Discovery of 5-Amino- N -(1 H -pyrazol-4-yl)pyrazolo[1,5- a ]pyrimidine-3-carboxamide Inhibitors of IRAK4
Journal Article · Thu Jun 11 00:00:00 EDT 2015 · ACS Medicinal Chemistry Letters · OSTI ID:1404964
Efforts towards the optimization of a bi-aryl class of potent IRAK4 inhibitors
Journal Article · Thu Sep 01 00:00:00 EDT 2016 · Bioorganic and Medicinal Chemistry Letters · OSTI ID:1404961

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES
Amines
Inhibitors
Monomers
Noncovalent interactions
Peptides and proteins