Abstract
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.
Highlights
Acute lung injury (ALI), characterized by increased permeability of endothelium and epithelium as well as loss of vascular integrity, is an acute inflammatory disease with high morbidity and mortality[1,2]
Several studies have shown that various inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a), play a pivotal role in the development and progrossion of ALI9–11
The blocked membranes were incubated with the indicated primary antibodies at 4 C overnight (All of the antibodies were purchased from Cell Signaling Technology, USA)
Summary
Acute lung injury (ALI), characterized by increased permeability of endothelium and epithelium as well as loss of vascular integrity, is an acute inflammatory disease with high morbidity and mortality[1,2]. Several studies have shown that various inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a), play a pivotal role in the development and progrossion of ALI9–11. Pyrazolopyrimidine moiety is an important drug-like scaffold[14], which have shown a wide range of clinical applications including bruton’s tyrosine kinase inhibitor ibrutinib (I)[15], tumor necrosis factor receptor-associated protein 1 (TRAP1) inhibitor (II)[16], cyclin-dependent kinase (CDK) inhibitors (III, IV)[17,18], anti-inflammation (V)[19] and bumped kinase inhibitors (VI, Figure 1)[20]. Some analogs exhibited anti-inflammatory activity in RAW 264.7 macrophage cells. In order to find potent anti-inflammatory agents, the scaffold was further modified and evaluated for their inhibitory effect against LPS-induced NO production in RAW264.7 macrophages (Figure 2)
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