Novel SNPs in a candidate gene, CRTH2, for allergic diseases

Hsu, Shih-Chang; Lc, Chen; Kuo, Min-Liang; Huang, Jing‐Long; Sk, Huang

doi:10.1038/sj.gene.6363826

Cited by 14 publications

(7 citation statements)

References 7 publications

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“…Single-nucleotide polymorphisms in DP2 are linked to asthma severity and associated with increased risk of atopy, including allergic rhinitis and wheeze (Hsu et al, 2002;Huang et al, 2004;Seibert et al, 2008). In our guinea pig model of allergic asthma, AM211 demonstrated significant inhibition of ovalbumin-induced inflammatory cell influx into bronchial alveolar lavage fluids.…”

Section: Discussionmentioning

confidence: 81%

Pharmacology of AM211, a Potent and Selective Prostaglandin D₂Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation

Bain¹,

Lorrain²,

Stebbins³

et al. 2011

J Pharmacol Exp Ther

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The prostaglandin D 2 (PGD 2 ) receptor type 2 (DP2) is a G protein-coupled receptor that has been shown to be involved in a variety of allergic diseases, including allergic rhinitis, asthma, and atopic dermatitis. In this study, we describe the preclinical pharmacological and pharmacokinetic properties of the smallmolecule DP2 antagonist [2Ј-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4Ј-trifluoromethyl-biphenyl-3-yl]-acetic acid (AM211). We determine that AM211 has high affinity for human, mouse, rat, and guinea pig DP2 and it shows selectivity over other prostanoid receptors and enzymes. Antagonist activity of AM211 at the DP2 receptor was confirmed by inhibition of PGD 2 -stimulated guanosine 5Ј-O-[␥-thio]triphosphate binding to membranes expressing human DP2. A basophil activation assay and a whole-blood assay of eosinophil shape change were used to demonstrate the ability of AM211 to potently antagonize PGD 2 -stimulated functional responses in relevant human cells and in the context of a physiologically relevant environment. AM211 exhibits good oral bioavailability in rats and dogs and dose-dependently inhibits 13,14-dihydro-15-keto-PGD 2 -induced leukocytosis in a guinea pig pharmacodynamic assay. AM211 demonstrates efficacy in two animal models of allergic inflammation, including an ovalbumin-induced lung inflammation model in guinea pigs and an ovalbumin-induced mouse model of allergic rhinitis. AM211 represents a potent and selective antagonist of DP2 that may be used clinically to evaluate the role of DP2 in T helper 2-driven allergic inflammatory diseases.

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Section: Discussionmentioning

confidence: 81%

Pharmacology of AM211, a Potent and Selective Prostaglandin D₂Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation

Bain¹,

Lorrain²,

Stebbins³

et al. 2011

J Pharmacol Exp Ther

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“…CRTH2 also mediates chemotaxis of Th2 lymphocytes, eosinophils and basophils towards PGD2 (7). There is evidence to suggest that genetic alteration of CRTH2 is related to allergic asthma in African‐American (8) and Chinese populations (8–12). There has been no published data addressing the role of the CRTH2 gene in aspirin exacerbated respiratory disease (AERD) pathogenesis.…”

mentioning

confidence: 99%

Genetic variability in CRTH2 polymorphism increases eotaxin‐2 levels in patients with aspirin exacerbated respiratory disease

Palikhe¹,

Kim²,

Cho

et al. 2010

Allergy

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“…The CRTH2 gene is located on the long arm (q) of chromosome 11 (11q12). Interestingly, some genetic studies linked the CRTH2 gene with traits of allergic diseases and asthma [15, 16]. CRTH2 mRNA has been detected in virtually all tissues of the human body.…”

Section: Dp and Crth2 Receptorsmentioning

confidence: 99%

Targeting the PGD2/CRTH2/DP1 Signaling Pathway in Asthma and Allergic Disease: Current Status and Future Perspectives

Kupczyk

Kuna

2017

Drugs

100

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Prostaglandin D2 (PGD2) released by degranulating mast cells is believed to play a key role in orchestrating mechanisms of inflammation in allergies and asthma. The biological effects of PGD2 are mediated by D-prostanoid (DP1), CRTH2 (DP2), and thromboxane prostanoid (TP) receptors. The CRTH2 receptor is involved in induction of migration and activation of T helper type 2 (Th2) lymphocytes, eosinophils, and basophils; up-regulation of adhesion molecules; and promotion of pro-inflammatory Th2-type cytokines (interleukin [IL]-4, 5, 13), whereas the DP receptor is associated with relaxation of smooth muscles, vasodilation, inhibition of cell migration, and apoptosis of eosinophils. A number of CRTH2/PGD2 receptor antagonists have been investigated in asthma and allergic diseases. The CRTH2 antagonist (OC000459) or dual CRTH2 and TP receptor antagonist (ramatroban) were effective in reducing eosinophilia, nasal mucosal swelling, and clinical symptoms of allergic rhinitis, with the latter drug registered for clinical use in this indication. OC000459 and setipiprant reduced the late but not early phase of response in an allergen challenge in atopic asthmatics. In persistent asthma, some molecules induced limited improvement in lung function, quality of life, and asthma symptoms (OC000459, BI671800), but in other trials with AMG 853 and AZ1981 these findings were not confirmed. The clear discrepancy between animal studies and clinical efficacy of CRTH2 antagonism in allergic rhinitis, and lack of efficacy in a general cohort of asthmatics, highlight the issue of patient phenotyping. There is no doubt that the PGD2/CATH2/DP1 pathway plays a key role in allergic inflammation and further studies with selective or combined antagonisms in well defined cohorts of patients are needed.

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Novel SNPs in a candidate gene, CRTH2, for allergic diseases

Cited by 14 publications

References 7 publications

Pharmacology of AM211, a Potent and Selective Prostaglandin D₂Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation

Pharmacology of AM211, a Potent and Selective Prostaglandin D₂Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation

Genetic variability in CRTH2 polymorphism increases eotaxin‐2 levels in patients with aspirin exacerbated respiratory disease

Targeting the PGD2/CRTH2/DP1 Signaling Pathway in Asthma and Allergic Disease: Current Status and Future Perspectives

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Novel SNPs in a candidate gene, CRTH2, for allergic diseases

Cited by 14 publications

References 7 publications

Pharmacology of AM211, a Potent and Selective Prostaglandin D2Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation

Pharmacology of AM211, a Potent and Selective Prostaglandin D2Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation

Genetic variability in CRTH2 polymorphism increases eotaxin‐2 levels in patients with aspirin exacerbated respiratory disease

Targeting the PGD2/CRTH2/DP1 Signaling Pathway in Asthma and Allergic Disease: Current Status and Future Perspectives

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Product

Resources

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Pharmacology of AM211, a Potent and Selective Prostaglandin D₂Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation

Pharmacology of AM211, a Potent and Selective Prostaglandin D₂Receptor Type 2 Antagonist That Is Active in Animal Models of Allergic Inflammation