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

Wenqiang Zhai; Yongping Lu; Yabo Zhu; Mengguang Zhou; Cheng Ye; Zheng-Zheng Shi; Wenjian Qian; Taishan Hu; Lei Chen

doi:10.1016/j.bmcl.2020.127686

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. Epub 2020 Nov 24.

Authors

Wenqiang Zhai¹, Yongping Lu¹, Yabo Zhu¹, Mengguang Zhou¹, Cheng Ye¹, Zheng-Zheng Shi¹, Wenjian Qian², Taishan Hu¹, Lei Chen¹

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: wjqian@hisunpharm.com.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amines / chemical synthesis
Amines / chemistry
Amines / pharmacology*
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Arthritis, Experimental / chemically induced
Arthritis, Experimental / drug therapy*
Arthritis, Experimental / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Haplorhini
Humans
Indazoles / chemical synthesis
Indazoles / chemistry
Indazoles / pharmacology*
Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors*
Interleukin-1 Receptor-Associated Kinases / metabolism
Lipopolysaccharides / antagonists & inhibitors
Mice
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Rats
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / biosynthesis

Substances

Amines
Anti-Inflammatory Agents, Non-Steroidal
Indazoles
Lipopolysaccharides
Protein Kinase Inhibitors
Tumor Necrosis Factor-alpha
IRAK4 protein, human
Interleukin-1 Receptor-Associated Kinases