用于治疗炎症的基于喹唑啉的 IRAK4 抑制剂的鉴定。
Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation.
作者信息
Smith Graham F, Altman Michael D, Andresen Brian, Baker James, Brubaker Jason D, Chen Hongmin, Chen Yiping, Childers Matthew, Donofrio Anthony, Ferguson Heidi, Fischer Christian, Fischmann Thierry O, Gibeau Craig, Hicks Alexander, Jin Sue, Kattar Sam, Kleinschek Melanie A, Leccese Erica, Lesburg Charles, Li Chaomin, Lim Jongwon, Liu Duan, Maclean John K F, Mansoor Faruk, Moy Lilly Y, Mulrooney Erin F, Necheva Antoaneta S, Presland Jeremy, Rakhilina Larissa, Yang Ruojing, Torres Luis, Zhang-Hoover Jie, Northrup Alan
机构信息
AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, United States.
Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
出版信息
Bioorg Med Chem Lett. 2017 Jun 15;27(12):2721-2726. doi: 10.1016/j.bmcl.2017.04.050. Epub 2017 Apr 18.
Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity. These highly selective IRAK4 compounds show activity in vivo via oral dosing in a TLR7 driven model of inflammation.
白细胞介素-1受体相关激酶4（IRAK4）参与基于IL-1R和TLR的信号传导。因此，选择性抑制该蛋白的激酶活性是治疗炎症性疾病的一个有吸引力的靶点。借助基于结构的药物设计对高通量筛选（HTS）命中化合物进行药物化学优化，从而鉴定出具有优异药代动力学特征和激酶选择性的口服生物可利用的喹唑啉类IRAK4抑制剂。这些高选择性的IRAK4化合物在由TLR7驱动的炎症模型中通过口服给药在体内显示出活性。
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