Pharmacology of MK-0591 (3-[1-(4-chlorobenzyl)-3-(<i>t</i>-butylthio)-5-(quinolin-2-yl-methoxy)-indol-2-yl]-2,2-dimethyl propanoic acid), a potent, orally active leukotriene biosynthesis inhibitor

Brideau, Christine; Chen, Chan; Deschênes, Denis; Evans, Jillian F.; Ford‐Hutchinson, A. W.; Fortin, Réjean; Gillard, John W.; Guay, Jocelyne; Guévremont, Diane; Hutchinson, John H.; Jones, Tom R.; Léger, Serge; Mancini, Joseph A.; Mcfarlane, C. S.; Pickett, Cecil B.; Piechuta, H.; Prasit, Petpiboon; Riendeau, Denis; Rouzer, Carol A.; Tagari, Philip; Vickers, Philip J.; Young, Robert N.; Abraham, William M.

doi:10.1139/y92-107

Cited by 110 publications

(66 citation statements)

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“…However, a clear-cut late increase in urinary LTE 4 has not yet been shown in humans [42]. In animal models, on the other hand, where acute responses of higher magnitude can be elicited, a continuous release of cys-LTs may be detected ( [43] and present results).…”

Section: Discussionmentioning

confidence: 52%

Allergen-induced late-phase airways obstruction in the pig: mediator release and eosinophil recruitment

Fornhem

Kumlin²,

Jm³

et al. 1995

Eur Respir J

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A Al ll le er rg ge en n--i in nd du uc ce ed d l la at te e--p ph ha as se e a ai ir rw wa ay ys s o ob bs st tr ru uc ct ti io on n i in n t th he e p pi ig g: : m me ed di ia at to or r r re el le ea as se e a an nd d e eo os si in no op ph hi il l r re ec cr ru ui it tm me en nt t ABSTRACT: The aim of this study was to develop a novel model for studies of mediator mechanisms involved in the late asthmatic reaction in the lower airways, by using the sensitized pig. The release of histamine and cysteinyl-containing leukotrienes (cys-LTs), as well as the levels of inflammatory cells in blood and bronchoalveolar lavage fluid, were determined and their relationship to plasma cortisol levels and pulmonary airways obstruction was noted. Specific-pathogen free pigs were actively sensitized with Ascaris suum allergen, and one group of animals was treated with a cortisol-synthesis inhibitor (metyrapone) by constant intravenous infusion. Ascaris suum allergen was nebulized into the lower airways and total lung resistance, blood leucocyte count and urinary levels of methylhistamine and leukotriene E 4 (LTE 4 ) were followed for 8 h, whereafter bronchoalveolar lavage was performed for analysis of leucocytes.An increase in urinary methylhistamine and LTE 4 was seen during the acute allergic reaction in both groups of pigs. Metyrapone treatment prolonged the acute release of histamine, and this was seen together with a prolonged acute bronchoconstrictor response. In metyrapone-treated pigs, a continuous release over 8 h was seen for cys-LTs, but not for histamine. A late blood eosinophilia was also seen in metyrapone-treated animals, starting 4-6 h after allergen challenge. Late cys-LT release and eosinophilia were absent in non-metyrapone-treated animals.These results suggest that allergen-induced late release of cys-LTs as well as blood eosinophilia occur simultaneously with late-phase airways obstruction in the pig, and that all these reactions are prevented by high levels of endogenous cortisol. Eur Respir J., 1995Respir J., , 8, 1100Respir J., -1109 The association between increased numbers of eosinophils in the lung and human bronchial asthma was shown by ELLIS [1] in 1908, and is today well-established. However, the exact mechanism of action of eosinophils and the relevance of the eosinophilia sometimes seen in asthma are not yet fully understood. We wanted to establish a large animal model for studies of the initiation of allergic inflammation in the airways, and the pig has been found to be suitable for such studies [2][3][4].The mast cell plays a pivotal role in the acute asthmatic response, in that it releases mediators, such as histamine and cysteinyl-containing leukotrienes (cys-LTs) [5]. Measurements of free levels of histamine and cysLTs in plasma may be difficult, due to uncontrolled release from blood leucocytes. Therefore, the relatively stable urinary end-metabolites methylhistamine [6] and leukotriene E 4 (LTE 4 ) [7], respectively, were measured in this study. The possible involvement of cys-LTs in t...

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Section: Discussionmentioning

confidence: 52%

Allergen-induced late-phase airways obstruction in the pig: mediator release and eosinophil recruitment

Fornhem

Kumlin²,

Jm³

et al. 1995

Eur Respir J

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“…In addition to indole structures, quinolines and hybrid structures of indoles and quinolines were found to bind FLAP and to inhibit LT biosynthesis in intact cells. Obviously, these FLAP inhibitors are potent blockers of LT synthesis in isolated PMNL, whereas in whole blood assays the drugs are 50-to 200-fold less active [86], [87], possibly due to high plasma protein binding of the drugs and/or competition with AA and other fatty acids for binding to FLAP [88].…”

Section: Molecular Pharmacology Of 5-lipoxygenase Inhibitorsmentioning

confidence: 99%

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

Werz¹

2007

Planta Med

155

135

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The biosynthesis of leukotrienes (LTs) is initiated by the transformation of free arachidonic acid to LTA 4 by 5-lipoxygenase (5-LO). Subsequent enzymatic conversion of LTA 4 yields LTB 4 and the cysteinyl-LTs C 4 , D 4 and E 4 . LTs have prominent functions in pathophysiology and are connected to numerous disorders including bronchial asthma, allergic rhinitis, inflammatory bowel and skin diseases, rheumatoid arthritis, cancer, osteoporosis and cardiovascular diseases. Pharmacological and genetic interruption of the 5-LO pathway or blockade of LT receptors, serving as means for intervention with LTs, may be of therapeutic value for certain related disorders. Natural or plant-derived substances were among the first 5-LO inhibitors identified in the early 1980 s. To date, a huge number of diverse plant-derived compounds have been reported to interfere with 5-LO product synthesis. However, many investigations have addressed the efficacy of a given compound solely in cellular test systems and analysis of direct interference with 5-LO has been neglected. In the first part of this review, the biology and molecular pharmacology of the 5-LO pathway is summarized in order to understand its overall regulation and complexity as well as to comprehend the possible points of attack of compounds that eventually lead to inhibition of 5-LO product formation in intact cells. In the second part, natural compounds that interfere with 5-LO product formation are compiled and grouped into structural classes, and the underlying molecular mechanisms and structureactivity relationships are discussed.

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“…2 and Table 2; Refs. 16 -20) with distinct SAR relative to previously reported indole-containing FLAP inhibitors exemplified by MK-886, MK-591, and AM-803 (15,21,22). Unexpectedly, we found that the biaryl amino-heteroarenes lacked activity in rodent whole blood ex vivo and in vivo models.…”

Section: -Lipoxygenase Activating Protein (Flap)mentioning

confidence: 47%

A Single Amino Acid Difference between Mouse and Human 5-Lipoxygenase Activating Protein (FLAP) Explains the Speciation and Differential Pharmacology of Novel FLAP Inhibitors

Blevitt

Hack

Herman

et al. 2016

Journal of Biological Chemistry

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On that basis, we tested compounds for binding to human G24A and mouse A24G FLAP mutant variants and compared the data to that generated for wild type human and mouse FLAP. These studies confirmed that a single amino acid mutation was sufficient to reverse the speciation observed in wild type FLAP. In addition, a PK/PD method was established in canines to enable preclinical profiling of mouse-inactive compounds. 5-Lipoxygenase activating protein (FLAP)2 is a key accessory protein in the arachidonic acid metabolism pathway (1). Its function is to present arachidonic acid to 5-lipoxygenase for conversion to leukotriene A 4 and subsequently present leukotriene A 4 to leukotriene C 4 synthase to generate the potent pro-inflammatory mediator leukotriene C 4 (2-4). Because of this critical role in the biosynthesis of leukotrienes, FLAP has been the subject of multiple drug discovery efforts (5, 6), with several inhibitors reaching proof of concept in small clinical trials (7-9).FLAP was originally identified via phenotypic screening for 5-lipoxygenase inhibitors and was described as an 18-kDa membrane protein (10). During the course of that effort, the compound MK-886 was found to bind to the FLAP polypeptide (11). Subsequently, the FLAP cDNA was cloned from multiple species, revealing high sequence homology (12, 13) (Fig. 1). X-ray crystallographic evidence indicated that FLAP exists as a homotrimer, similar to other members of the MAPEG family, with each monomer containing four transmembrane ␣-helices (14). A major compound binding site is embedded within the membrane, formed by the interface of ␣-helices 2 and 4 of one monomer and ␣-helix 1 of the adjacent monomer (14), resulting in three binding sites per trimer. Mutational analysis revealed several key interactions with the FLAP inhibitor MK-591, aiding in the understanding of its binding mode and SAR surrounding this series of indoles (15).During our own high throughput screening efforts, we discovered benzimidazoles and a series of biaryl amino-heteroarenes ( Fig. 2 and Table 2; Refs. 16 -20) with distinct SAR relative to previously reported indole-containing FLAP inhibitors exemplified by 21,22). Unexpectedly, we found that the biaryl amino-heteroarenes lacked activity in rodent whole blood ex vivo and in vivo models. Here we propose that a single amino acid difference in the binding pocket that is conserved in murine, rat, and porcine FLAP is sufficient to render compounds of this series inactive in these species, based on ligand displacement analysis, whole blood activity assays, and computational studies. Because rodents are commonly used for pharmacokinetic and pharmacodynamics studies, we established an alternative path for the preclinical profiling of biaryl amino-heteroarenes and related compounds in canines. Experimental ProceduresPreparation of was suspended in a 2:1 mixture of N,N-dimethylformamide and water to a total volume of 1.5 ml, followed by addition of 34 mg (5 equivalents) of hydroxybenzotriazole, 10 mg (1 equivalent) of 1-ethyl-3-(3-dimeth...

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Pharmacology of MK-0591 (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-yl-methoxy)-indol-2-yl]-2,2-dimethyl propanoic acid), a potent, orally active leukotriene biosynthesis inhibitor

Cited by 110 publications

References 0 publications

Allergen-induced late-phase airways obstruction in the pig: mediator release and eosinophil recruitment

Allergen-induced late-phase airways obstruction in the pig: mediator release and eosinophil recruitment

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

A Single Amino Acid Difference between Mouse and Human 5-Lipoxygenase Activating Protein (FLAP) Explains the Speciation and Differential Pharmacology of Novel FLAP Inhibitors

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