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 IC_(50) values less than 1 mmol/L in cell-based assays.Here,we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fusedring 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 andin 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. 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 IC 50 values ​​less than 1 mmol / L in cell-based assays. Here, we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fusedring system. New compounds showed 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 i n 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.