Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases

Pettipher, Roy; Hansel, Trevor T.; Armer, Richard

doi:10.1038/nrd2266

Cited by 287 publications

(317 citation statements)

References 104 publications

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“…This inhibition has been achieved with ramatroban, marketed for allergic rhinitis, which blocks the TP receptor (this receptor binds thromboxane A2) and the chemoattractant receptor-homologous molecule that is expressed on Th2 lymphocytes (CRTH2; receptor for prostaglandin D2) in parallel 115 . Modulation of leukotriene action has also been shown to be effective against asthma and allergic rhinitis: zileton targets 5-LO with a limited potency, whereas montelukast, pranlukast and zafirlukast interfere with the action of cysteinyl leukotrienes (leukotrienes C4, D4 and E4) on cysteinyl leukotriene-1 and -2 receptors 116,117 .…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%

Lipid signalling in disease

Wymann

Schneiter

2008

Nat Rev Mol Cell Biol

1,126

906

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Section: Therapeutic Opportunitiesmentioning

confidence: 99%

Lipid signalling in disease

Wymann

Schneiter

2008

Nat Rev Mol Cell Biol

1,126

906

View full text Add to dashboard Cite

“…La PGD2 induit la production d'histamine puis une vasodilatation dans la muqueuse nasale, une bronchoconstriction et le recrutement et l'activation des lymphocytes Th2 et des éosinophiles via les récepteurs DP1, TP et CRTH2 respectivement [21,22]. Les deux récepteurs DP1 et CRTH2 ont donc des rôles complémentaires dans la médiation de la réponse allergique [23].…”

Section: Les Rôles De La Prostaglandine D2unclassified

“…La production de PGD2 par les mastocytes est un processus dépendant des deux isoformes COX1 et COX2, et pourtant les anti-inflammatoires non stéroïdiens sont inefficaces dans le traitement de l'asthme allergique. Ces médicaments pourraient en fait inhiber la production de PGE2 qui antagonise l'effet de la PGD2 par ses propriétés bronchodilatatrices [22]. Ces différentes données obtenues chez l'animal ont été validées par l'identification de variants génétiques de DP1 et CRTH2 chez des patients ayant une prédisposition allergique [22].…”

Section: Les Rôles De La Prostaglandine D2unclassified

“…Ces médicaments pourraient en fait inhiber la production de PGE2 qui antagonise l'effet de la PGD2 par ses propriétés bronchodilatatrices [22]. Ces différentes données obtenues chez l'animal ont été validées par l'identification de variants génétiques de DP1 et CRTH2 chez des patients ayant une prédisposition allergique [22].…”

Section: Les Rôles De La Prostaglandine D2unclassified

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La prostaglandine D2

Malki

Declosmenil²,

Farhat³

et al. 2008

Med Sci (Paris)

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“…This has created significant interest in both DP-1 and CRTH 2 as targets, and several publications have appeared describing inhibitor design. 10,11 PGD 2 is synthesized from arachidonic acid via the oxidation by cyclooxygenase PGH 2 (COX) and isomerization of PGH 2 to PGD 2 by prostaglandin D synthase (PGDS). Hematopoietic PGDS (HPGDS) is responsible for the synthesis of PGD 2 by mast cells and Th-2 cells, whereas a lipocalin type PGDS (LPGDS) catalyzes the production of PGD 2 in the central nervous system, male genital organs, and heart.…”

mentioning

confidence: 99%

Discovery of an Oral Potent Selective Inhibitor of Hematopoietic Prostaglandin D Synthase (HPGDS)

Carron

Trujillo

et al. 2010

ACS Med. Chem. Lett.

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Hematopoietic prostaglandin D synthase (HPGDS) is primarly expressed in mast cells, antigen-presenting cells, and Th-2 cells. HPGDS converts PGH 2 into PGD 2 , a mediator thought to play a pivotal role in airway allergy and inflammatory processes. In this letter, we report the discovery of an orally potent and selective inhibitor of HPGDS that reduces the antigen-induced response in allergic sheep.KEYWORDS Hematopoietic prostaglandin D synthase (HPGDS), PGH 2 , PGD 2 , airway allergy, inflammatory processes, cyclooxygenase (COX) A sthma is a chronic inflammatory disorder of the airways that causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing in susceptible individuals. 1,2 Prostaglandin D 2 (PGD 2 ), a mediator of allergy and inflammation, is produced by mast cells and Th-2 cells in a variety of human tissues. PGD 2 is the most abundant de novo cyclooxygenase-derived mediator produced following IgE-mediated degranulation of mast cells. 3 The mast cell, following allergen-provoked degranulation, is believed to be the major source of PGD 2 found in the nasal exudates of patients with allergic rhinitis. PGD 2 levels increase dramatically in bronchoalveolar lavage fluid following allergen challenge, and the observation that patients with asthma exhibit bronchoconstriction upon inhalation of PGD 2 underscores the pathologic consequences of high levels of PGD 2 in the lung. 4 Treatment with PGD 2 produces significant nasal congestion and fluid secretion in man and dogs, and PGD 2 is 10 times more potent than histamine and 100 times more potent than bradykinin in producing nasal blockage in humans, demonstrating a role for PGD 2 in allergic rhinitis. 5,6 Mast cell-derived PGD 2 exerts its effect by activating two distinct G-protein-coupled receptors (GPCRs): the DP-1 receptor, a member of the prostanoid receptor subfamily, and the recently discovered chemoattractant receptor-homologous molecule expressed on T-helper 2 cells (CRTH 2 receptor). The DP-1 receptor is localized on the nasal vasculature and in mucin-secreting cells and is associated with tissue swelling and a concomitant increase in nasal airway resistance, while the CRTH 2 receptor is expressed on a subset of infiltrating T cells in inflamed nasal mucosa and is associated with the induction of chemotactic migration and/or activation of Th-2, eosinophils, and basophils. 7-9 Collectively, these data support a role for PGD 2 in inflammatory diseases of the upper airways and suggest that blockade of PGD 2 action at either or both receptors might be beneficial for the treatment of nasal allergies and other PGD 2 -mediated inflammatory conditions. This has created significant interest in both DP-1 and CRTH 2 as targets, and several publications have appeared describing inhibitor design. 10,11 PGD 2 is synthesized from arachidonic acid via the oxidation by cyclooxygenase PGH 2 (COX) and isomerization of PGH 2 to PGD 2 by prostaglandin D synthase (PGDS). Hematopoietic PGDS (HPGDS) is responsible for the synthesis of PGD 2 b...

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Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases

Cited by 287 publications

References 104 publications

Lipid signalling in disease

Lipid signalling in disease

La prostaglandine D2

Discovery of an Oral Potent Selective Inhibitor of Hematopoietic Prostaglandin D Synthase (HPGDS)

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