Discovery and optimization of a potent and selective indazolamine series of IRAK4 inhibitors

  • Bioorg Med Chem Lett. 2021 Jan 1;31:127686. doi: 10.1016/j.bmcl.2020.127686.
Wenqiang Zhai  1 ,  Yongping Lu  1 ,  Yabo Zhu  1 ,  Mengguang Zhou  1 ,  Cheng Ye  1 ,  Zheng-Zheng Shi  1 ,  Wenjian Qian  2 ,  Taishan Hu  1 ,  Lei Chen  1
Affiliations
  • 1. Zhejiang Hisun Pharmaceutical Co. Ltd., China, 46 Waisha Rd., Taizhou 318099, China.
  • 2. Zhejiang Hisun Pharmaceutical Co. Ltd., China, 46 Waisha Rd., Taizhou 318099, China. Electronic address: [email protected].
PMID: 33242574 DOI: 10.1016/j.bmcl.2020.127686
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.

Keywords
Collagen-induced arthritis; IRAK4; Indazole; Inflammation; TNFα.
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