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Discovery and Structure Enabled Synthesis of 2,6-Diaminopyrimidin-4-one IRAK4 Inhibitors

Journal Article · · ACS Medicinal Chemistry Letters
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  1. Merck Research Lab., Kenilworth, NJ (United States)
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We report the identification and synthesis of a series of aminopyrimidin-4-one IRAK4 inhibitors. Through high throughput screening, an aminopyrimidine hit was identified and modified via structure enabled design to generate a new, potent, and kinase selective pyrimidin-4-one chemotype. This chemotype is exemplified by compound 16, which has potent IRAK4 inhibition activity (IC50 = 27 nM) and excellent kinase selectivity (>100-fold against 99% of 111 tested kinases), and compound 31, which displays potent IRAK4 activity (IC50 = 93 nM) and good rat bioavailability (F = 42%).

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Organization:
USDOE
OSTI ID:
1404979
Journal Information:
ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 8 Vol. 6; ISSN 1948-5875
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (15)

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Advances in the Discovery of Small-Molecule IRAK4 Inhibitors book January 2014
Ligand efficiency: a useful metric for lead selection journal May 2004
Identification and optimization of indolo[2,3-c]quinoline inhibitors of IRAK4 journal May 2014
Discovery and hit-to-lead optimization of 2,6-diaminopyrimidine inhibitors of interleukin-1 receptor-associated kinase 4 journal May 2015
Initial optimization and series evolution of diaminopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 journal August 2015
IRAK-4 – a shared NF-κB activator in innate and acquired immunity journal December 2006
The kinase activities of interleukin-1 receptor associated kinase (IRAK)-1 and 4 are redundant in the control of inflammatory cytokine expression in human cells journal April 2009
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
Molecular Structure of an Isocytosine Analog: Combined X-ray Structural and Computational Study of 2-Diethylamino-6-methyl-5-n-propyl-4(3H)-pyrimidinone journal January 1999
Targeting innate immunity protein kinase signalling in inflammation journal June 2009
Toll-like receptor signalling journal July 2004
Signalling mechanisms for Toll-like receptor-activated neutrophil exocytosis: key roles for interleukin-1-receptor-associated kinase-4 and phosphatidylinositol 3-kinase but not Toll/IL-1 receptor (TIR) domain-containing adaptor inducing IFN-β (TRIF) journal July 2009
Pyogenic Bacterial Infections in Humans with IRAK-4 Deficiency journal March 2003
IRAK4 Kinase Activity Is Required for Th17 Differentiation and Th17-Mediated Disease journal June 2009

Cited By (5)

Graphene Oxide-Based Nanocomposites Decorated with Silver Nanoparticles as an Antibacterial Agent journal April 2018
Design of a Novel and Selective IRAK4 Inhibitor Using Topological Water Network Analysis and Molecular Modeling Approaches journal November 2018
Conformational flexibility and inhibitor binding to unphosphorylated interleukin-1 receptor–associated kinase 4 (IRAK4) journal January 2019
Synthesis of 2-Cyanopyrimidines journal October 2019
BindingDB Entry 50046641: Discovery and Structure Enabled Synthesis of 2,6-Diaminopyrimidin-4-one IRAK4 Inhibitors. dataset January 2016

Figures / Tables (7)

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

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES
Inhibitors
Peptides and proteins
Piperidines
Pyrimidine
Selectivity