Discovery of potent CRTh2 (DP2) receptor antagonists

Agonist and Antagonist Effects of 15R-Prostaglandin (PG) D2and 11-Methylene-PGD2on Human Eosinophils and Basophils

“…Minor structural modification of ramatroban resulted in a highly selective and potent DP 2 antagonist (Ulven and Kostenis, 2005). Other indolic compounds with selective DP 2 receptor antagonist activities have also recently been reported (Armer et al, 2005;Birkinshaw et al, 2006). A series of tetrahydroquinoline derivatives have also been identified as selective DP 2 antagonists (Mimura et al, 2005).…”

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

“…Indomethacin has also provided a template for DP 2 blockers, based to some extent on its weak agonism for the DP 2 receptor (Hirai et al, 2002;Stubbs et al, 2002). Many of these analogs are designed around an inverted indole template (Birkinshaw et al, 2006). This latter profile may be due to slow dissociation from the DP 2 receptor (Mathiesen et al, 2006).…”

Ligand Based HQSAR Analysis of CRTh2 Antagonists

“…There is also evidence that genetic alterations of CRTh2 are linked to increased risk of allergy or asthma [10] . It is well established that antagonizing selectively the CRTh2 receptor could be useful in the treatment of asthma and other inflammatory disease [1,2,6,7] . Hologram Quantitative Structure Activity Relationship (HQSAR) is the novel 2D fragment-based QSAR method that employs specialized molecular fingerprints [11,12] and eliminates the need for 3D structure, molecular alignment and conformational search [13,14] .…”

“…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] .…”

“…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] .…”