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

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 compound 29 which exhibited sub-micromolar potency in a LTA stimulated cellular assay.

Authors:
; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1400285
Resource Type:
Journal Article
Resource Relation:
Journal Name: Bioorganic and Medicinal Chemistry Letters; Journal Volume: 27; Journal Issue: 21
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

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, and Poss, Michael A. Discovery and structure-based design of 4,6-diaminonicotinamides as potent and selective IRAK4 inhibitors. United States: N. p., 2017. Web. doi:10.1016/j.bmcl.2017.09.029.
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. Discovery and structure-based design of 4,6-diaminonicotinamides as potent and selective IRAK4 inhibitors. United States. doi:10.1016/j.bmcl.2017.09.029.
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, and Poss, Michael A. Wed . "Discovery and structure-based design of 4,6-diaminonicotinamides as potent and selective IRAK4 inhibitors". United States. doi:10.1016/j.bmcl.2017.09.029.
@article{osti_1400285,
title = {Discovery and structure-based design of 4,6-diaminonicotinamides as potent and selective IRAK4 inhibitors},
author = {Bhide, Rajeev S. and Keon, Alec and Weigelt, Carolyn and Sack, John S. and Schmidt, Robert J. and Lin, Shuqun and Xiao, Hai-Yun and Spergel, Steven H. and Kempson, James and Pitts, William J. and Carman, Julie and Poss, Michael A.},
abstractNote = {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.},
doi = {10.1016/j.bmcl.2017.09.029},
journal = {Bioorganic and Medicinal Chemistry Letters},
number = 21,
volume = 27,
place = {United States},
year = {Wed Nov 01 00:00:00 EDT 2017},
month = {Wed Nov 01 00:00:00 EDT 2017}
}