Leukotriene B₄receptor antagonists as therapeutics for inflammatory disease: preclinical and clinical developments

Abstract

Leukotriene B(4) (LTB(4)) is a lipid inflammatory mediator derived from membrane phospholipids by the sequential actions of cytosolic phospholipase A2 (PLA2), 5-lipoxygenase (5-LO) and leukotriene A(4) (LTA(4)) hydrolase. Several inflammatory diseases, including asthma, chronic obstructive pulmonary disease, arthritis and inflammatory bowel disease, have been associated with elevated levels of LTB(4). As a result, pharmacological strategies to modulate the synthesis of LTB(4) (inhibition of PLA2, 5-LO or LTA(4) hydrolase) or the effects of LTB(4) itself (antagonism of LTB(4) receptors) are being developed by several companies. Two G-protein-coupled receptors mediate the effects of LTB(4), namely BLT1 and BLT2. The pharmacology, expression and function of these two receptors were last reviewed by Tager and Luster in 2004. Since then, there has been an increased understanding of the function of these receptors, in particular for the lesser understood of the two receptors, BLT2. Furthermore, since last reviewed in 1996, there have been several clinical developments in the use of BLT receptor antagonists for inflammatory diseases. This review summarizes the latest preclinical and clinical developments in BLT antagonism for inflammatory diseases and discusses potential future developments.

BLT2 is expressed in PanINs, IPMNs, pancreatic cancer and stimulates tumour cell proliferation

“…The expected background signal in normal pancreas should be sufficiently low, because acinar and islet cells only showed weak positive staining in some tissues and BLT2 mRNA levels in whole pancreas are very low compared with other organs. Finally, development of a combined BLT1 and BLT2 antagonist (Hicks et al, 2007) could be a valuable approach for the treatment and chemoprevention of pancreatic and perhaps other cancers.…”

Role of Leukotriene B4 in 5-Lipoxygenase Metabolite- and Allergy-Induced Itch-Associated Responses in Mice

“…8) In addition, Biomed-101, a potent LTB 4 receptor antagonist, may prevent the formation of edema caused by interleukin-2 (IL-2) therapy in clinical trials. 20) These reports suggest that LTB 4 may be involved in edema formation in certain diseases. However, our present results suggest that LTB 4 has little effect on vascular permeability in allergic reactions.…”

Emerging anti-inflammatory strategies for COPD

“…The effects of LTB 4 are mediated by two G-protein-coupled receptors termed BLT1 and BLT2 [94]. Classically, BLT1 mediates LTB 4 -evoked neutrophil and macrophage migration to sites of inflammation via chemotaxis and upregulation of adhesion molecules (e.g.…”