Discovery and optimization of a potent and selective indazolamine series of IRAK4 inhibitors. (1st January 2021)

• Record Type: Journal Article
• Authors: Zhai, Wenqiang; Lu, Yongping; Zhu, Yabo; Zhou, Mengguang; Ye, Cheng; Shi, Zheng-Zheng; Qian, Wenjian; Hu, Taishan; Chen, Lei
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 31(2021)
• Publication Date: 2021-01-01
• Subjects: IRAK4 -- Inflammation -- Indazole -- TNFα -- Collagen-induced arthritis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127686
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: IRAK4 is a key mediator of innate immunity. There is a high interest in identifying novel IRAK4 inhibitors for the treatment of inflammatory autoimmune diseases. We describe here a highly potent and selective IRAK4 inhibitor (HS271) that exhibited superior enzymatic and cellular activities, as well as excellent pharmacokinetic properties. HS271 displayed robust in vivo anti-inflammatory efficacy as evaluated in rat models of LPS induced TNFα production and collagen-induced arthritis.