ABSTRACT
Human 5-lipoxygenase (5-LOX) is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders. Our previous work on structural optimization of the hit compound 2 from our in-house collection identified two lead compounds, 3a and 3b, exhibiting a potent inhibitory profile against 5-LOX with IC50 values less than 1 µmol/L in cell-based assays. Here, we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fused-ring system. Several new compounds exhibited more potent inhibitory activity than the lead compounds against 5-LOX. In particular, compound 4e not only suppressed lipopolysaccharide-induced inflammation in brain inflammatory cells and protected neurons from oxidative toxicity, but also significantly decreased infarct damage in a mouse model of cerebral ischemia. Molecular docking analysis further confirmed the consistency of our theoretical results and experimental data. In conclusion, the excellent in vitro and in vivo inhibitory activities of these compounds against 5-LOX suggested that these novel chemical structures have a promising therapeutic potential to treat leukotriene-related disorders.
ABSTRACT
Objective To investigate the changes of serum apolipoprotein A-I and its clinical significance to acute respiratory infection.Method Totally 44 patients with acute respiratory infection were divided into three groups according to various concentration of Serum apolipoprotein A-I.They were procaleitonin(PCT)＜0.5 ng/ml group,0.5 ng/ml≤PCT＜2 ng/ml group and PCT≥2 ng/ml group.We measured apolipoprotein A-I,C-reactive protein,procalcitonin and albumin within 24 hours after admission.Results With the increase of serumPCT,the production of ApoA-I and albumin were down-regulated,while CRP up-regulated.Conclusions Apolipoprotein A-I has a sound relationship with the acute respiratory infection.It can be used as one of the diagnostic criteria in severe infection patients who have disorders of lipometabolism.