Discovery and structure-based design of 4,6-diaminonicotinamides as potent and selective IRAK4 inhibitors

[Display omitted] The identification of small molecule inhibitors of IRAK4 for the treatment of autoimmune diseases has been an area of intense research. We discovered novel 4,6-diaminonicotinamides which potently inhibit IRAK4. Optimization efforts were aided by X-ray crystal structures of inhibito...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2017-11, Vol.27 (21), p.4908-4913
Hauptverfasser:	Bhide, Rajeev S., Keon, Alec, Weigelt, Carolyn, Sack, John S., Schmidt, Robert J., Lin, Shuqun, Xiao, Hai-Yun, Spergel, Steven H., Kempson, James, Pitts, William J., Carman, Julie, Poss, Michael A.
Format:	Artikel
Sprache:	eng
Schlagworte:	4,6-Diaminonicotinamide 60 APPLIED LIFE SCIENCES Autoimmune disease BASIC BIOLOGICAL SCIENCES Binding Sites Crystallography, X-Ray Drug Design Drug Evaluation, Preclinical Humans Inhibitory Concentration 50 Interleukin-1 Receptor-Associated Kinases - antagonists & inhibitors Interleukin-1 Receptor-Associated Kinases - metabolism IRAK4 Janus Kinase 3 - chemistry Janus Kinase 3 - metabolism Molecular Conformation Molecular Dynamics Simulation Niacinamide - chemistry Niacinamide - metabolism Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - metabolism Protein Structure, Tertiary Rheumatoid arthritis Structure-Activity Relationship
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Zusammenfassung:	[Display omitted] The identification of small molecule inhibitors of IRAK4 for the treatment of autoimmune diseases has been an area of intense research. We discovered novel 4,6-diaminonicotinamides which potently inhibit IRAK4. Optimization efforts were aided by X-ray crystal structures of inhibitors bound to IRAK4. Structure activity relationship (SAR) studies led to the identification of compound 29 which exhibited sub-micromolar potency in a LTA stimulated cellular assay.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2017.09.029