Leukotriene B4 receptor antagonists as therapeutics for inflammatory disease: preclinical and clinical developments.
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.
Department of Inflammation Discovery, 340 Kingsland Street, Nutley, New Jersey, NJ 07110, USA. alexandra.hicks@roche.com
Alexandra
A
Hicks
Seth P
SP
Monkarsh
Ann F
AF
Hoffman
Robert
R
Goodnow
D000818:Animals; D002986:Clinical Trials as Topic / Q000379:methods / Q000639:trends; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000639:trends; D015507:Drugs, Investigational / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D015507:Drugs, Investigational; D018102:Receptors, Leukotriene B4