2. Academic Validation
  3. Discovery of orally active 1,4,5,6,8-pentaazaacenaphthylens as novel, selective, and potent covalent BTK inhibitors for the treatment of rheumatoid arthritis

Discovery of orally active 1,4,5,6,8-pentaazaacenaphthylens as novel, selective, and potent covalent BTK inhibitors for the treatment of rheumatoid arthritis

  • Eur J Med Chem. 2022 Nov 25;246:114940. doi: 10.1016/j.ejmech.2022.114940.
Xiaobao Fang 1,  Chunxiao Liu 2,  Kun Zhang 1,  Wanping Yang 1,  Zewen Wu 1,  Shige Shen 2,  Yule Ma 1,  Xun Lu 1,  Yadong Chen 3,  Tao Lu 4,  Qinghua Hu 5,  Yulei Jiang 6
Affiliations

Affiliations

  • 1 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China.
  • 2 School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China.
  • 3 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: ydchen@cpu.edu.cn.
  • 4 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: lutao@cpu.edu.cn.
  • 5 School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China. Electronic address: huqh@cpu.edu.cn.
  • 6 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China. Electronic address: jiangyulei@cpu.edu.cn.
PMID: 36462441 DOI: 10.1016/j.ejmech.2022.114940
Abstract

Bruton's tyrosine kinase (Btk) plays a crucial role in adaptive and immune responses by modulating B-cell, Fc, toll-like, and Chemokine Receptor signaling pathways. Btk inhibition is a promising therapeutic approach for the treatment of inflammatory and autoimmune diseases. The development of novel, highly selective, and less toxic Btk inhibitors may be beneficial for the treatment of autoimmune diseases with unmet medical needs. In this study, structure-based drug design was used to discover a series of novel, potent, and selective covalent Btk inhibitors with a 1,4,5,6,8-pentaazaacenaphthylen scaffold. Among them, compound 36R exhibited high kinase selectivity, long target occupancy time, appropriate pharmacokinetic properties, and dose-dependent efficacy in a rat model of collagen-induced arthritis. Therefore, 36R is a novel Btk Inhibitor requiring further development for the treatment of autoimmune diseases.

Keywords

1,4,5,6,8-Pentaazaacenaphthylens scaffold; Autoimmune disease treatment; BTK inhibitor; Kinase selectivity.

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