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Chemical Reviews Oct 2011
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Journal of Medicinal Chemistry Jul 1996
Review
Topics: 5-Lipoxygenase-Activating Proteins; Animals; Carrier Proteins; Forecasting; Humans; Leukotriene B4; Leukotrienes; Lipoxygenase Inhibitors; Membrane Proteins; Molecular Structure; Receptors, Leukotriene
PubMed: 8709092
DOI: 10.1021/jm960088k -
Life Sciences Jun 2002Cysteinyl-leukotrienes, i.e. leukotriene (LT) C4, D4 and E4, are inflammatory mediators and potent airway- and vasoconstrictors. Two different cysteinyl-leukotriene... (Review)
Review
Cysteinyl-leukotrienes, i.e. leukotriene (LT) C4, D4 and E4, are inflammatory mediators and potent airway- and vasoconstrictors. Two different cysteinyl-leukotriene receptors, CysLT1 and CysLT2, have been cloned and functionally characterised using potent CysLT1 receptor antagonists and the dual CysLT1/CysLT2 receptor antagonist BAY u9773. However, the rank order of potency of the cysteinyl-leukotrienes at the CysLT receptors differs between tissues and studies, and a CysLT receptor classification based on agonist selectivity has not been established. In addition, the existence of more than two receptor subtypes for cysteinyl-leukotrienes has been suggested.
Topics: Animals; Asthma; Blood Vessels; Cysteine; Humans; Inflammation Mediators; Leukotriene D4; Leukotrienes; Membrane Proteins; Receptors, Leukotriene; Vasoconstriction; Vasoconstrictor Agents
PubMed: 12072150
DOI: 10.1016/s0024-3205(02)01733-2 -
American Journal of Respiratory and... Jun 1998Several strategies have been employed by medicinal chemists in the design of potent and selective leukotriene receptor antagonists-leukotriene structural analogs, FPL... (Review)
Review
Several strategies have been employed by medicinal chemists in the design of potent and selective leukotriene receptor antagonists-leukotriene structural analogs, FPL 55712 analogs, and random screening of corporate compound banks. Lead compounds were optimized, often through the exchange of ideas with groups working on other chemical series of leukotriene antagonists. Pranlukast can likely be traced to a lead compound identified by random screening that was initially modified by incorporating structural components present in FPL 55712. Montelukast originated from an early quinoline lead, which was modified with leukotriene structural elements. Zafirlukast is based on a lead compound that incorporated structural components from both FPL 55712 and the leukotrienes. Therefore, each medicinal chemistry strategy that was originally employed has successfully identified clinically effective leukotriene receptor antagonists.
Topics: Acetates; Anti-Asthmatic Agents; Biological Availability; Chromones; Cyclopropanes; Indoles; Leukotriene Antagonists; Leukotrienes; Lipoxygenase Inhibitors; Phenylcarbamates; Quinolines; SRS-A; Structure-Activity Relationship; Sulfides; Sulfonamides; Tosyl Compounds
PubMed: 9647603
DOI: No ID Found -
Cellular and Molecular Life Sciences :... May 2002Leukotrienes are a family of paracrine hormones derived from the oxidative metabolism of arachidonic acid. These lipid mediators are recognized as important signal... (Review)
Review
Leukotrienes are a family of paracrine hormones derived from the oxidative metabolism of arachidonic acid. These lipid mediators are recognized as important signal molecules in a variety of inflammatory and allergic conditions affecting the skin, joints, gastrointestinal and respiratory systems, in particular asthma. Such conditions are typified by local pain, tissue edema, hyperemia and functional losses. In the tissues, immunocompetent cells accumulate at the site of injury which contribute to tissue damage and perpetuation of the disease process. Leukotrienes can elicit most, if not all, of these signs and symptoms. Thus, leukotriene B4 is one of the most powerful chemotactic agents known to date and participates in the recruitment of leukocytes. The cysteinyl leukotrienes, on the other hand, contract smooth muscles, particularly in the peripheral airways and microcirculation. Recently, drugs which block the formation and action of leukotrienes have been introduced as novel antiasthmatic medications. This chapter reviews the biochemistry, molecular biology and cell biology of the key enzymes and cognate receptors in the leukotriene cascade.
Topics: 5-Lipoxygenase-Activating Proteins; Animals; Arachidonate 5-Lipoxygenase; Carrier Proteins; Epoxide Hydrolases; Humans; Leukocytes; Leukotrienes; Membrane Lipids; Membrane Proteins; Models, Biological; Molecular Structure; Phospholipases A; Receptors, Leukotriene; Signal Transduction
PubMed: 12088275
DOI: 10.1007/s00018-002-8463-1 -
Bioorganicheskaia Khimiia Jun 1993The review covers the aspects of classification, specificity and structure--biological activity relations in leukotriene receptor antagonists which blockade the action... (Review)
Review
The review covers the aspects of classification, specificity and structure--biological activity relations in leukotriene receptor antagonists which blockade the action of the acyclic arachidonate metabolites. Prospects of designing new medicines based on these compounds are also discussed.
Topics: Drug Antagonism; Drug Design; Leukotrienes; Receptors, Immunologic; Receptors, Leukotriene; Receptors, Leukotriene B4
PubMed: 8395845
DOI: No ID Found -
Tanpakushitsu Kakusan Koso. Protein,... Apr 2000
Review
Topics: Arachidonic Acid; Chromones; Drug Design; Humans; Indoles; Leukotriene Antagonists; Leukotrienes; Membrane Proteins; Phenylcarbamates; Receptors, Leukotriene; SRS-A; Sulfonamides; Tosyl Compounds
PubMed: 10771659
DOI: No ID Found -
The Journal of Asthma : Official... 1996A role for the leukotrienes in asthma has been postulated for many years. These mediators induce potent bronchoconstriction, stimulate mucous secretion and decrease... (Review)
Review
A role for the leukotrienes in asthma has been postulated for many years. These mediators induce potent bronchoconstriction, stimulate mucous secretion and decrease mucus transport, increase vascular permeability (thereby promoting edema formation), and induce migration of eosinophils into the lung. Recent studies with both leukotriene receptor antagonists and leukotriene synthesis inhibitors have demonstrated that these new agents can be effective in asthma induced by exercise, aspirin, and allergen challenges. Further, in patients with mild-to-moderate asthma, these drugs improve pulmonary function, decrease symptoms, and reduce the need for "rescue" bronchodilators. Anti-leukotrienes thus represent an important step forward in asthma management.
Topics: Asthma; Leukotriene Antagonists; Leukotrienes
PubMed: 8968291
DOI: 10.3109/02770909609068181 -
TheScientificWorldJournal Jun 2002The leukotrienes are a family of lipid mediators involved in inflammation and allergy. Leukotriene B4 is a classical chemoattractant, which triggers adherence and... (Review)
Review
The leukotrienes are a family of lipid mediators involved in inflammation and allergy. Leukotriene B4 is a classical chemoattractant, which triggers adherence and aggregation of leukocytes to the endothelium at only nM concentrations. In addition, leukotriene B4 modulates immune responses, participates in the host defense against infections, and is a key mediator of PAF-induced lethal shock. Because of these powerful biological effects, leukotriene B4 is implicated in a variety of acute and chronic inflammatory diseases, e.g., nephritis, arthritis, dermatitis, and chronic obstructive pulmonary disease. The final step in the biosynthesis of leukotriene B4 is catalyzed by leukotriene A4 hydrolase, a unique bifunctional zinc metalloenzyme with an anion-dependent aminopeptidase activity. Here we describe the most recent developments regarding our understanding of the function and molecular architecture of leukotriene A4 hydrolase.
Topics: Catalysis; Chemotactic Factors; Epoxide Hydrolases; Leukotrienes; Models, Molecular; Protein Structure, Quaternary; Structure-Activity Relationship
PubMed: 12806167
DOI: 10.1100/tsw.2002.810 -
Pharmacotherapy Sep 2008Abstract Chronic obstructive pulmonary disease (COPD) is characterized by progressive, irreversible airflow limitation coupled with an abnormal inflammatory process. It... (Review)
Review
Abstract Chronic obstructive pulmonary disease (COPD) is characterized by progressive, irreversible airflow limitation coupled with an abnormal inflammatory process. It is associated with high morbidity and mortality. Leukotriene modifiers, approved by the United States Food and Drug Administration as treatment for asthma and allergic rhinitis, may also alleviate the abnormal inflammatory response seen in patients with COPD. To explore the outcomes of research in this area, we conducted a literature search from 1950-2007, using the PubMed database. We found no published studies that provided conclusive evidence that the available leukotriene modifiers benefit patients with COPD. However, data do suggest that leukotriene modifiers may offer benefits to patients with COPD, including effects that pertain to airflow limitation, neutrophil and lymphocyte chemotaxis, and neutrophil longevity. Added to conventional treatment, these agents appear to reduce symptoms, improve objective measures of disease, and control inflammation. Further studies are needed to determine the precise role of leukotriene modifiers in the treatment of COPD.
Topics: Animals; Clinical Trials as Topic; Humans; Leukotriene Antagonists; Leukotrienes; Pulmonary Disease, Chronic Obstructive
PubMed: 18752388
DOI: 10.1592/phco.28.9.1183