Journal of Enzyme Inhibition and Medicinal Chemistry (Jan 2019)

Design and synthesis of novel pyrazolo[4,3-d]pyrimidines as potential therapeutic agents for acute lung injury

  • Bao Shi Wang,
  • Xin Huang,
  • Liu Zeng Chen,
  • Ming Ming Liu,
  • Jing Bo Shi

DOI
https://doi.org/10.1080/14756366.2019.1618291
Journal volume & issue
Vol. 34, no. 1
pp. 1121 – 1130

Abstract

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Four series of total 35 new pyrazolo[4,3-d]pyrimidine compounds were designed, synthesized and evaluated for their inhibitory activity against LPS-induced NO production in RAW264.7 macrophages. Among them, compound 4e was found to be the most potent inhibitor, which decreased the production of cytokines in vitro, such as NO, IL-6 and TNF-α, with IC50 values of 2.64, 4.38 and 5.63 μM, respectively. Further studies showed that compound 4e inhibited cytokines secretion of macrophages through suppressing TLR4/p38 signaling pathway. Additionally, compound 4e showed in vivo anti-inflammatory activity in LPS-induced model of acute lung injury. These data suggested that compound 4e may be a promising lead structure for the treatment of ALI.

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