基于结构设计发现4,6-二氨基烟酰胺作为有效的选择性IRAK4抑制剂。
Discovery and structure-based design of 4,6-diaminonicotinamides as potent and selective IRAK4 inhibitors.
作者信息
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
机构信息
Discovery Chemistry, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08543, United States.
Discovery Chemistry, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08543, United States.
出版信息
Bioorg Med Chem Lett. 2017 Nov 1;27(21):4908-4913. doi: 10.1016/j.bmcl.2017.09.029. Epub 2017 Sep 18.
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.
寻找用于治疗自身免疫性疾病的 IRAK4 小分子抑制剂一直是一个深入研究的领域。我们发现了能有效抑制 IRAK4 的新型 4,6 - 二氨基烟酰胺。与 IRAK4 结合的抑制剂的 X 射线晶体结构有助于优化研究工作。构效关系（SAR）研究确定了化合物 29，它在 LTA 刺激的细胞试验中表现出亚微摩尔级的效力。
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