Modulators of Leukotriene Biosynthesis and Receptor Activation

Abstract

IntroductionThe history of leukotriene (LT) research has been documented in numerous articles and reviews since the discovery of the LT biosynthetic pathway 1 and the delineation of the various chemical structures involved in the pathway and their total synthesis. 2 Three previous Perspective articles have provided periodic updates, the first in 1981, 3 the second 1 decade later covering LT receptor antagonists, 4 and the third in 1992 covering LT biosynthesis inhibitors. 5 With this background, the task of this Perspective is to update the status of LT intervention research by providing an overview of the leading enzyme inhibitors and receptor antagonists as well as the status of clinical trials with these agents and how the latter are influencing the development of new therapeutic modalities for the treatment of inflammation and allergy.The clinical proof-of-concept for LT intervention has taken longer than expected considering that the biosynthesis and chemical composition of LTs were delineated by 1979. It is now clear that LT intervention therapy represents a promising new modality for the treatment of asthma. Several compounds including the 5-lipoxygenase (5-LO) inhibitor zileuton (1) and the cysteinyl LT antagonist zafirlukast (2) have completed pivotal clinical trials, while several other LT modulators are progressing to this stage. Within a few years the therapeutic potential of these new agents in asthma and other inflammatory and allergic disorders will be evident. Leukotriene Intervention StrategiesLeukotriene Biosynthesis. Leukotrienes are biosynthesized via the 5-LO (arachidonate:oxygen 5-oxidoreductase, EC 1.13.11.34) pathway of arachidonic acid (AA) metabolism ( Figure 1). The 5-LO product LTA 4 is a pivotal reactive epoxide intermediate in an important branch in the biosynthetic pathway that is further metabolized by either (i) stereoselective hydration by LTA 4 hydrolase to LTB 4 or (ii) glutathione addition by LTC 4 synthase to LTC 4 . Successive amino acid cleavage steps convert LTC 4 to LTD 4 and then to LTE 4 . The cysteinyl LTs (LTC 4 , LTD 4 , LTE 4 ) are the constituents of the biological substance previously known as slowreacting substance of anaphlyaxis (SRS-A). 6 LTB 4 is a very potent neutrophil chemotactic agent, inducing neutrophil adherence to endothelial cells, degranulation, and modulation of cytokine production. The biosynthesis, release, and recovery of LTs from specific cells involved in inflammatory disorders together with the observed ability of these products to mimic aspects of disease support their involvement as mediators of inflammatory and allergic disorders. 7,8 Despite such circumstantial evidence, confirmation of the pathophysiological role of these mediators requires selective blockade of their actions.At the outset of research efforts in the LT area, it was not entirely clear which LTs or subsequent metabolites were the predominant mediators of a particular human disorder. LTs are short-lived, being rapidly converted to inactive metabolites, and prolonged expressi...

Essential fatty acids and the brain: possible health implications

“…With the discovery that several classes of lipid have profound eects on cell Both prostaglandins and leukotrienes act in a paracrine and autocrine form on cell function through a family of transmembrane receptors [20,126] regulating numerous aspects of cell functions. In addition, experimental evidence supports the position that the eicosanoid compounds are also involved in a range of physiological and pathological processes, including vascular [93], immunological [44,52] and in¯ammatory [96] responses.…”

“…In addition, increased Ca 2+ levels also activate PLA 2 , releasing AA from membrane phospholipids [9]. Leukotrienes, like prostaglandins, act through G-protein-coupled transmembrane receptors [20]. Although the distribution of 5-lipoxygenase is restricted to certain myeloid cells, LTB 4 is secreted by other cells because the enzymes capable of catalyzing the conversion of LTB 4 to other leukotrienes are widely distributed in tissues [10,20].…”

“…Leukotrienes, like prostaglandins, act through G-protein-coupled transmembrane receptors [20]. Although the distribution of 5-lipoxygenase is restricted to certain myeloid cells, LTB 4 is secreted by other cells because the enzymes capable of catalyzing the conversion of LTB 4 to other leukotrienes are widely distributed in tissues [10,20]. In fact LTB 4 has been identi®ed in in¯ammatory exudates in arthritis [142] and cystic ®brosis [71] and in the epidermis of patients with psoriasis [141].…”

FORMATION AND PROTEIN BINDING OF THE ACYL GLUCURONIDE OF A LEUKOTRIENE B4ANTAGONIST (SB-209247): RELATION TO SPECIES DIFFERENCES IN HEPATOTOXICITY

“…In the case of SB-209247, however, the inflammation apparently neither requires induction by persistent hepatocellular necrosis nor results in such damage in most cases. As a highaffinity selective antagonist of LTB 4 binding to neutrophils (Daines et al, 1996), SB-209247 would be expected to block any LTB 4 -mediated neutrophilic sequestration in response to drug-induced liver injury (Fretland et al, 1995;Brooks and Summers, 1996;Davis et al, 2000). The inhibitory activities of the drug's metabolites are unknown; the ether glucuronide of one LTB 4 receptor antagonist (BIIL 284) does retain considerable pharmacological activity (Birke et al, 2001).…”

“…Male rats were given doses of SB-209247 that produced maximum plasma concentrations similar to those attained in the dogs, but no pathological changes were found in their livers. The etiology of the hepatopathy in dogs is unknown: an influx of inflammatory cells is a common response to hepatocellular injury, although it is superficially paradoxical in this case because LTB 4 receptor antagonists inhibit, particularly, the chemotaxis of neutrophils and, inter alia, their accumulation in skin (Brooks and Summers, 1996). Hepatic adverse reactions attributable to the various types of leukotriene antagonist are not unknown in experimental animals and humans, but there is presently no clear evidence for a generic association related to either pharmacological activity or the presence of a carboxylic acid function (Fretland et al, 1995;Chambers et al, 1999;Reinus et al, 2000).…”