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

被引：16

作者：

Bhide, Rajeev S. ^{[1
]}

Keon, Alec ^{[1
]}

Weigelt, Carolyn ^{[2
]}

Sack, John S. ^{[2
]}

Schmidt, Robert J. ^{[1
]}

Lin, Shuqun ^{[1
]}

Xiao, Hai-Yun ^{[1
]}

Spergel, Steven H. ^{[1
]}

Kempson, James ^{[1
]}

Pitts, William J. ^{[1
]}

Carman, Julie ^{[3
]}

Poss, Michael A. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Discovery Chem, Res & Dev, Route 206 & Prov Line Rd, Princeton, NJ 08543 USA

[2] Bristol Myers Squibb Co, Mol Struct & Design, Res & Dev, Route 206 & Prov Line Rd, Princeton, NJ 08543 USA

[3] Bristol Myers Squibb Co, Immunosci Biol, Res & Dev, Route 206 & Prov Line Rd, Princeton, NJ 08543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2017年 / 27卷 / 21期

关键词：

IRAK4; 4,6-Diaminonicotinamide; Rheumatoid arthritis; Autoimmune disease; KINASE; 4; IRAK4; IMMUNITY; DISEASES; INNATE;

D O I：

10.1016/j.bmcl.2017.09.029

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：4908 / 4913

页数：6

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