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

Journal Article · Wed Nov 01 00:00:00 EDT 2017 · Bioorganic and Medicinal Chemistry Letters

DOI:https://doi.org/10.1016/j.bmcl.2017.09.029· OSTI ID:1400285

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.

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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: INDUSTRY
• OSTI ID: 1400285
• Journal Information: Bioorganic and Medicinal Chemistry Letters, Journal Name: Bioorganic and Medicinal Chemistry Letters Journal Issue: 21 Vol. 27; ISSN 0960-894X
• Publisher: Elsevier
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES