Recent development of lipoxygenase inhibitors as anti-inflammatory agents

Abstract

Inflammation is favorable in most cases, because it is a kind of body defensive response to external stimuli; sometimes, inflammation is also harmful, such as attacks on the body's own tissues. It could be that inflammation is a unified process of injury and resistance to injury. Inflammation brings extreme pain to patients, showing symptoms of rubor, swelling, fever, pain and dysfunction. As the specific mechanism is not clear yet, the current anti-inflammatory agents are given priority for relieving suffering of patients. Thus it is emergent to find new anti-inflammatory agents with rapid effect. Lipoxygenase (LOX) is a kind of rate-limiting enzyme in the process of arachidonic acid metabolism into leukotriene (LT) which mediates the occurrence of inflammation. The inhibition of LOX can reduce LT, thereby producing an anti-inflammatory effect. In this review, the LOX inhibitors reported in recent years are summarized, and, in particular, their activities, structure-activity relationships and molecular docking studies are emphasized, which will provide new ideas to design novel LOX inhibitors.

The role of 5-lipoxygenase in the pathophysiology of COVID-19 and its therapeutic implications

“…BRP-187 has shown to be a potent inhibitor of LT biosynthesis in-vitro and in-vivo, by blocking 5-LOX/FLAP complex assembly in activated human monocytes and polymorphonuclear leukocytes (PMNs) and an inhibitor of the microsomal PGE2 synthase 1 [108,109]. AM803 (currently known as GSK2190915) is a FLAP inhibitor that potently inhibits the formation of LTB4 and is currently under investigation in clinical trials [108].…”

“…The molecular structure of LOX and the complex nature of the involvement of LT in the initiation and resolution of inflammation, have not been yet clearly understood. This could be one of the reasons that several LOX inhibitors are not approved for clinical use [109]. Combination of 5-LOX/ LT inhibitors that can act on upstream or downstream mediators of the inflammatory pathways, can be used as an effective treatment option to abort acute inflammation in various diseases [110].…”

Development of pyrazole derivatives in the management of inflammation

“…The chemical structure and biological targets are important clues for identifying pyrazole derivatives with potential anti‐inflammatory activity [23,86,87]. Over the years, the attachment of important functional groups to the pyrazole ring was used to create derivatives [22,88,89].…”

Platelet-type 12-lipoxygenase deletion provokes a compensatory 12/15-lipoxygenase increase that exacerbates oxidative stress in mouse islet β cells

“…The observation that Alox15 levels are elevated in Alox12 Ϫ/Ϫ islets also highlights a deficiency in our understanding of the regulation of the genes encoding LOX enzymes. As inhibitors of LOX enzymes begin to gain traction for disease modification (32,41), it will be especially relevant to understand how inhibition of specific enzymes might influence the expression and activities of other related LOXs. Future studies unraveling the effect of complete loss versus inhibition of a lipoxygenase enzyme and possible compensatory effects are thus warranted.…”