Leukotrienes model

Toward the synthesis of leukotriene model compounds, combinations of appropriately substituted alkenyl halides and alkenylstannanes have been used in this three-component reaction applied to norbomadiene (Scheme 6). ... 

The first SRS-A antagonist, FPL-55712 (26) (149), was discovered before the stmctures of the leukotrienes were detemiined. Although this compound is relatively weak as an antagonist and suffers from a very short half-life in vivo, it played an important role both in leukotriene stmcture elucidation and as a model for later antagonists. In work stmcturaHy related to FPL-55712, LY-171883 was developed (27) (150). LY-171883 was evaluated in several clinical trials before development was stopped. Orally adrninistered, LY-171883 blocked slightly the response to aerosol LTD improved pulmonary function (FEV ) in mild asthmatics (151), decreased the sensitivity of asthmatics to cold air-induced bronchoconstriction (152), and significantly reduced the bronchoconstrictor response to inhaled antigen (153). However, in all these studies the beneficial effects were minimal. 

While the obvious value of in vivo animal models is clear, there also are instances—especially in cases of inflammatory arthritis, behavior, and tumor growth—where they have failed to be predictive of useful clinical activity in humans [51], For example, leukotriene (LTB4) antagonists showed activity in animal models of inflammatory arthritis yet failed to be useful in rheumatoid arthritis [52]. Similarly, dopamine D4 antagonists showed activity in animal behavior models previously predictive of dopamine D2 antagonists in schizophrenia. However, testing of dopamine D4 antagonists showed no efficacy in humans [53]. 

Compound 508 (PNRI-299), a small molecule /3-strand mimetic template compound, is active as an inhibitor of the multifunctional activating protein factor 1 (AP-1). PNRI-299 has demonstrable effects on the reduction of API-driven transcription and beneficial pharmacological effects in a mouse asthma model. The compound affects the expression of leukotriene C4 (LTC4) synthase, a crucial enzyme for the formation of the cysteinyl leukotrienes <2003PNA1169, 2004MI211>. 

Figure 4.1. Model of neurogenic inflammation. Stimulation at the skin initiates orthodromic impulses in sensory nerve receptors which elicit antidromic impulses in branching collaterals. The release of neuropeptides such as calcitonin gene-related peptide (CGRP), substance P (SP), and somatostatin (SOM) from nerve terminals ensues and they in turn stimulate the release of histamine (H) and the generation of leukotrienes (LT) from nearby mast cells. These mediators then produce vasodilatation and an increase in vascular permeability. In addition, they act on the nerve terminal to produce further...

The successful application of this method was illustrated with a series of model dienes, and with the formal synthesis of leukotriene A4 methyl ester, a complex polyene monoepoxide, from the intermediate epoxyundecadienoate 17 prepared by selective epoxidation of trienyl ester 16 (equation 17). 

Fig. 6.1 Schematic representation of the cysteinyl leukotriene 2 (CysLT ) receptor. Ribbon model of this family A G protein-coupled receptor (GPCR) is pictured in its heptahelical configuration. The extracellular amino terminus of the receptor, the transmembrane domains, and the intracellular carboxyl tail extend behind the intracellular palmitoylation site. The putative binding pocket for cysteinyl leukotriene ligands is derived from a rhodopsin model...

Fig. 8.2 Alignment of the protein structure of the cysteinyl leukotriene 1 (CysLTj) and 2 (CysLT ) receptors in relation to rhodopsin. The amino acids conserved between these family A receptors are shown. The consensus is greater than 50%. These data formed the basis of the model predicting the CysLTj and CysLT transmembrane domains (helices 1-7), the four [3-sheets, and the putative cysteinyl leukotiiene-binding domain. The amino acid variants that are associated with atopy or asthma, the G300S CysLTj variant, and the M201V CysLT variant are each boxed and noted with arrows...

Finally there has been a growing interest in the development of selective leukotriene inhibitors. Bay Y 1015 (R-(-)-2-cycloheptyl-N-methylsulfonyl-(4-(2-quinolinyl-methoxy) phenyl)-acetamide) is a quinoline-type 5-lipoxygenase-activating protein inhibitor which was effective in inhibiting inflammation in a dextran sulfate model of mouse colitis [112]. Whether these compounds can also exert their anti-inflammatory action through inhibition of endothelial cell activation needs to be established. 

The cysteinyl leukotrienes, particularly LTC4 and LTD4, are potent bronchoconstrictors and cause increased microvascular permeability, plasma exudation, and mucus secretion in the airways. Controversies exist over whether the pattern and specificity of the leukotriene receptors differ in animal models and humans. LTC4-specific receptors have not been found in human lung tissue, whereas both high- and low-affinity LTD4 receptors are present. 

Although they remain less effective than inhaled corticosteroids, a 5-LOX inhibitor (zileuton) and selective antagonists of the CysLTl receptor for leukotrienes (zafirlukast, montelukast, and pranlukast see Chapter 20) are used clinically in mild to moderate asthma. Growing evidence for a role of the leukotrienes in cardiovascular disease has expanded the potential clinical applications of leukotriene modifiers. Conflicting data have been reported in animal studies depending on the disease model used and the molecular target (5-LOX versus FLAP). Human genetic studies have demonstrated a link between cardiovascular disease and polymorphisms in the leukotriene biosynthetic enzymes, in particular FLAP, in some populations. 

Pygeum africanum, an extract from the bark of the African prune tree, has been used in Europe since 1969 to treat men with mild to moderate symptoms of benign prostatic hyperplasia. The mechanism of action of P. africanum is not known. In animal models, P. africanum modulates bladder contractility, has anti-inflammatory activity, decreases production of leukotrienes and other 5-lipoxygenase metabolites, inhibits fibroblast production, affects adrenal androgens, and restores the secretory activity of prostate epithelium. 

Dual inhibitors of COX and 5-LOX will not only suppress prostaglandins that contribute to acute inflammation conditions, but also address the accumulation of phagocytic leukotrienes that are directly associated with chronic inflammation symptoms. With the existence of COX-1 inhibition activities, dual inhibitors will also possess the cardio protective functions. Those characteristics suggest that there may be distinct advantages to dual inhibitors of COX and 5-LOX over selective COX-2 inhibitors and NSAIDs. This concept has been proved to be valid on in vivo models with synthetic drug candidates [105]. 

Fig. 1. A model for the pleiotropic effects of LH on functions of Leydig cells. LH interacts with its specific receptor in the plasma membrane of the Leydig cell which results in the activation of several transducing systems and the formation of several second messengers (cyclic AMP, Ca2+, diacylglycerol and arachidonic acid metabolites). Protein kinases (A, C and calmodulin dependent) are activated resulting in the phosphorylation of specific proteins and the synthesis of specific proteins. The (phospho)proteins are involved in the transport of cholesterol to, and the control of, cholesterol metabolism in the inner mitochondrial membrane. Arachidonic acid metabolites (prostaglandins, leukotrienes) may also control steroidogenesis. LH can also regulate the secretion of proteins. The trophic effects of LH are manifested in the growth and differentiation of the Leydig cells.

Oda et al. have reported a ternary coupling involving norbomadiene, a vinyltin and a vinyl iodide (Scheme 4-25), which is proposed as a model for leukotriene synthesis [71]. 

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