Update on the Development of Antagonists of Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2). From Lead Optimization to Clinical Proof-of-Concept in Asthma and Allergic Rhinitis

Pettipher, Roy; Whittaker, Mark

doi:10.1021/jm2013997

Cited by 70 publications

(59 citation statements)

References 75 publications

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“…In fact, the modest cough responses evoked by PGD 2 in this study and the interesting observation that DP 2 receptor activation may inhibit C-fibre discharge may suggest that a DP 2 receptor antagonist could enhance the cough responses evoked by PGD 2 . Since the discovery that DP 2 receptor antagonists could inhibit allergen-induced inflammation there has been a major focus for drug discovery in the asthma area over recent years and there are several compounds in clinical trials [16]. However, this data would suggest that caution should be exercised when developing DP 2 antagonists for asthma as preventing DP 2 receptor activation (especially when endogenous PGD 2 production is high as is possible in allergic diseases) may be detrimental and result in inappropriate stimulation of airway reflexes.…”

Section: Discussionmentioning

confidence: 99%

“…In recent years significant research effort has been directed into the pro-inflammatory effects of PGD 2 and evidence suggests that PGD 2 , via the DP 2 receptor, recruits inflammatory cells to the airways [14]. In line with these observations there are now several DP 2 antagonists being trialled for the treatment of asthma and allergic diseases [16]. PGD 2 has been shown to cause cough in preclinical studies and in clinical studies following nasal challenge [17,18].…”

Section: Introductionmentioning

confidence: 99%

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Prostaglandin D₂and the role of the DP₁, DP₂and TP receptors in the control of airway reflex events

et al. 2014

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Prostaglandin D 2 (PGD 2 ) causes cough and levels are increased in asthma suggesting that it may contribute to symptoms. Although the prostaglandin D 2 receptor 2 (DP 2 ) is a target for numerous drug discovery programmes little is known about the actions of PGD 2 on sensory nerves and cough.We used human and guinea pig bioassays, in vivo electrophysiology and a guinea pig conscious cough model to assess the effect of prostaglandin D 2 receptor (DP 1 ), DP 2 and thromboxane receptor antagonism on PGD 2 responses.PGD 2 caused cough in a conscious guinea pig model and an increase in calcium in airway jugular ganglia. Using pharmacology and receptor-deficient mice we showed that the DP 1 receptor mediates sensory nerve activation in mouse, guinea pig and human vagal afferents. In vivo, PGD 2 and a DP 1 receptor agonist, but not a DP 2 receptor agonist, activated single airway C-fibres. Interestingly, activation of DP 2 inhibited sensory nerve firing to capsaicin in vitro and in vivo.The DP 1 receptor could be a therapeutic target for symptoms associated with asthma. Where endogenous PGD 2 levels are elevated, loss of DP 2 receptor-mediated inhibition of sensory nerves may lead to an increase in vagally associated symptoms and the potential for such adverse effects should be investigated in clinical studies with DP 2 antagonists. @ERSpublications Prostaglandin D 2 activates sensory nerves and evokes cough via DP 1 receptors

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prostaglandin D₂and the role of the DP₁, DP₂and TP receptors in the control of airway reflex events

et al. 2014

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“…Prostaglandin D2 (PGD2), a major metabolite of arachidonic acid is produced in high quantities by mast cells, particularly during IgE-dependent allergic responses [1][2][3][4][5] . PGD2 exhibit its biological responses by activating two seven transmembrane (7TM) G-protein coupled receptors (GPCRs), the classical DP1 receptor and chemoattractant receptor-homologous molecule expressed on T-helper 2 cells (CRTh2 also known as DP2) receptor [1][2][3][4][5][6] .…”

Section: Introductionmentioning

confidence: 99%

“…PGD2 exhibit its biological responses by activating two seven transmembrane (7TM) G-protein coupled receptors (GPCRs), the classical DP1 receptor and chemoattractant receptor-homologous molecule expressed on T-helper 2 cells (CRTh2 also known as DP2) receptor [1][2][3][4][5][6] . CRTh2 is selectively expressed by Th2 cells, eosinophils and basophils and mediates chemotactic activation of these cells in response to prostaglandin D2 (PGD2) [1][2][3][4][5][6][7] . The interaction between immunologically activated mast cells and Th2 lymphocytes plays a key role in the pathogenesis of allergic disorders, and recent evidence suggests that CRTH2 plays a dominant role in mediating this interaction [2] and act as an important mediator in allergic reactions, including asthma, atopic dermatitis and allergic rhinitis [7][8][9] .…”

Section: Introductionmentioning

confidence: 99%

“…CRTh2 is selectively expressed by Th2 cells, eosinophils and basophils and mediates chemotactic activation of these cells in response to prostaglandin D2 (PGD2) [1][2][3][4][5][6][7] . The interaction between immunologically activated mast cells and Th2 lymphocytes plays a key role in the pathogenesis of allergic disorders, and recent evidence suggests that CRTH2 plays a dominant role in mediating this interaction [2] and act as an important mediator in allergic reactions, including asthma, atopic dermatitis and allergic rhinitis [7][8][9] . There is also evidence that genetic alterations of CRTh2 are linked to increased risk of allergy or asthma [10] .…”

Section: Introductionmentioning

confidence: 99%

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Ligand Based HQSAR Analysis of CRTh2 Antagonists

Babu¹,

Madhavan²

2015

Journal of the Chosun Natural Science

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CRTh2 receptor is an important mediator of the inflammatory effects and act as beneficial target for the treatment of asthma, COPD, allergic rhinitis and atopic dermatitis. In the present work, Hologram QSAR studies were conducted on a series of 50 training set CRTh2 antagonists (2-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl acetic acids). The best HQSAR model was obtained using atoms, bonds, connections and donor/acceptor as fragment distinction parameter using hologram length 257 and 6 components with fragment size of minimum 7 and maximum 10. Significant cross-validated correlation coefficient (q 2 =0.786) and non cross-validated correlation coefficients (r 2 =0. 954) were obtained. The model was then used to evaluate the 15 external test compounds which are not included in the training set and the predicted values were in good agreement with the experimental results (r 2 pred =0.739). Contribution map show that presence of C ring and its substituents makes big contributions for activities. The HQSAR model and analysis from the contribution map could be useful for further design of novel structurally related CRTh2 antagonists.

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Ring Opening of Donor–Acceptor Cyclopropanes with the Azide Ion: A Tool for Construction of N‐Heterocycles

Ivanov

Villemson

Будынина

et al. 2015

Chemistry A European J

145

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A general method for ring opening of various donor-acceptor cyclopropanes with the azide ion through an SN 2-like reaction has been developed. This highly regioselective and stereospecific process proceeds through nucleophilic attack on the more-substituted C2 atom of a cyclopropane with complete inversion of configuration at this center. Results of DFT calculations support the SN 2 mechanism and demonstrate good qualitative correlation between the relative experimental reactivity of cyclopropanes and the calculated energy barriers. The reaction provides a straightforward approach to a variety of polyfunctional azides in up to 91 % yield. The high synthetic utility of these azides and the possibilities of their involvement in diversity-oriented synthesis were demonstrated by the developed multipath strategy of their transformations into five-, six-, and seven-membered N-heterocycles, as well as complex annulated compounds, including natural products and medicines such as (-)-nicotine and atorvastatin.

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Update on the Development of Antagonists of Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2). From Lead Optimization to Clinical Proof-of-Concept in Asthma and Allergic Rhinitis

Cited by 70 publications

References 75 publications

Prostaglandin D₂and the role of the DP₁, DP₂and TP receptors in the control of airway reflex events

Prostaglandin D₂and the role of the DP₁, DP₂and TP receptors in the control of airway reflex events

Ligand Based HQSAR Analysis of CRTh2 Antagonists

Ring Opening of Donor–Acceptor Cyclopropanes with the Azide Ion: A Tool for Construction of N‐Heterocycles

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Update on the Development of Antagonists of Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2). From Lead Optimization to Clinical Proof-of-Concept in Asthma and Allergic Rhinitis

Cited by 70 publications

References 75 publications

Prostaglandin D2and the role of the DP1, DP2and TP receptors in the control of airway reflex events

Prostaglandin D2and the role of the DP1, DP2and TP receptors in the control of airway reflex events

Ligand Based HQSAR Analysis of CRTh2 Antagonists

Ring Opening of Donor–Acceptor Cyclopropanes with the Azide Ion: A Tool for Construction of N‐Heterocycles

Contact Info

Product

Resources

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Prostaglandin D₂and the role of the DP₁, DP₂and TP receptors in the control of airway reflex events

Prostaglandin D₂and the role of the DP₁, DP₂and TP receptors in the control of airway reflex events