Design, synthesis and biological study of BTK/JAK3 dual-target inhibitors

CEN Lifang; CHENG Ming; REN Weijie; YE Liu; WANG Luhua; GUO Weibo; ZHANG Qiang; XU Yungen

doi:10.11665/j.issn.1000-5048.2024010201

Journal of China Pharmaceutical University > 2024 > 55(1): 73-86. > DOI: 10.11665/j.issn.1000-5048.2024010201

CEN Lifang, CHENG Ming, REN Weijie, et al. Design, synthesis and biological study of BTK/JAK3 dual-target inhibitors[J]. J China Pharm Univ, 2024, 55(1): 73 − 86. DOI: 10.11665/j.issn.1000-5048.2024010201

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Design, synthesis and biological study of BTK/JAK3 dual-target inhibitors

CEN Lifang^{1, 共},
CHENG Ming^{1, 共},
REN Weijie¹,
YE Liu¹,
WANG Luhua¹,
GUO Weibo^{1, 2},
ZHANG Qiang²,
XU Yungen^1, ,

1.
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009
2.
Xi'an Xintong Pharmaceutical Research Co., Ltd, Xi’an 710077, China

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Received Date: January 01, 2024
Available Online: March 05, 2024

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Abstract

Abstract

In the present study, the compound XL-12 from our previous work was utilized as a lead compound. Through the optimization of the terminal phenyl ring, 12 target compounds were designed and synthesized. The structures of all target compounds were confirmed by ¹H NMR, ¹³C NMR, and H RMS. In vitro enzyme activity assay showed that most compounds demonstrated significant inhibitory activity toward Bruton’s tyrosine kinase (BTK) and Janus kinase 3 (JAK3). Among them, compound I-3 exhibited moderate cell proliferation inhibitory activity toward Daudi cells and BaF3-JAK3 cells. In the evaluation of anti-inflammatory activity in vitro, compound I-3 could effectively inhibit the production of inflammatory factors IL-6; besides, it exhibited superior anti-inflammatory activity compared to ibrutinib in xylene-induced ear swelling model in mice.
- rheumatoid arthritis,
- BTK inhibitor,
- JAK3 inhibitor,
- dual-target inhibitors,
- anti-inflammatory

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Design, synthesis and biological study of BTK/JAK3 dual-target inhibitors