Discovery and structure-based design of 4, 6-diaminonicotinamides as potent and selective IRAK4 inhibitors. Issue 21 (1st November 2017)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 21(2017)
• Page Start: 4908
• Page End: 4913
• Publication Date: 2017-11-01
• Subjects: IRAK4 -- 4, 6-Diaminonicotinamide -- Rheumatoid arthritis -- Autoimmune disease; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.09.029
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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 compound29 which exhibited sub-micromolar potency in a LTA stimulated cellular assay.