prostaglandin-d2 and fevipiprant

Prostaglandin D. Eosinophils and ILC2s were isolated from peripheral blood of atopic asthmatic patients. Eosinophil shape change, ILC2 migration and IL-5/IL-13 cytokine secretion were measured after stimulation with seven PGD. Selected metabolites induced eosinophil shape change with similar nanomolar potencies except for 9α,11β-PGF

Topics: Adolescent; Adult; Aged; Asthma; Cell Movement; Cell Shape; Cells, Cultured; Eosinophils; Female; Humans; Indoleacetic Acids; Interleukin-13; Interleukin-5; Lymphocytes; Male; Middle Aged; Prostaglandin Antagonists; Prostaglandin D2; Pyridines; Receptors, Immunologic; Receptors, Prostaglandin; Signal Transduction; Young Adult

The signaling of prostaglandin D

Topics: Carbazoles; Humans; Indoleacetic Acids; Ligands; Molecular Docking Simulation; Prostaglandin D2; Protein Binding; Pyridines; Receptors, G-Protein-Coupled; Receptors, Immunologic; Receptors, Prostaglandin; Signal Transduction; Sulfonamides

Here we describe the pharmacologic properties of a series of clinically relevant chemoattractant receptor-homologous molecules expressed on T-helper type 2 (CRTh2) receptor antagonists, including fevipiprant (NVP-QAW039 or QAW039), which is currently in development for the treatment of allergic diseases. [(3)H]-QAW039 displayed high affinity for the human CRTh2 receptor (1.14 ± 0.44 nM) expressed in Chinese hamster ovary cells, the binding being reversible and competitive with the native agonist prostaglandin D2(PGD2). The binding kinetics of QAW039 determined directly using [(3)H]-QAW039 revealed mean kinetic on (kon) and off (koff) values for QAW039 of 4.5 × 10(7)M(-1)min(-1)and 0.048 minute(-1), respectively. Importantly, thekoffof QAW039 (half-life = 14.4 minutes) was >7-fold slower than the slowest reference compound tested, AZD-1981. In functional studies, QAW039 behaved as an insurmountable antagonist of PGD2-stimulated [(35)S]-GTPγS activation, and its effects were not fully reversed by increasing concentrations of PGD2after an initial 15-minute incubation period. This behavior is consistent with its relatively slow dissociation from the human CRTh2 receptor. In contrast for the other ligands tested this time-dependent effect on maximal stimulation was fully reversed by the 15-minute time point, whereas QAW039's effects persisted for >180 minutes. All CRTh2 antagonists tested inhibited PGD2-stimulated human eosinophil shape change, but importantly QAW039 retained its potency in the whole-blood shape-change assay relative to the isolated shape change assay, potentially reflective of its relatively slower off rate from the CRTh2 receptor. QAW039 was also a potent inhibitor of PGD2-induced cytokine release in human Th2 cells. Slow CRTh2 antagonist dissociation could provide increased receptor coverage in the face of pathologic PGD2concentrations, which may be clinically relevant.

Topics: Acetates; Animals; Anti-Allergic Agents; Binding, Competitive; Cell Shape; Cells, Cultured; CHO Cells; Cricetulus; Drugs, Investigational; Eosinophils; Humans; Indoleacetic Acids; Indoles; Kinetics; Ligands; Prostaglandin D2; Pyridines; Receptors, Immunologic; Receptors, Prostaglandin; Recombinant Proteins; Solubility; Th2 Cells; Tritium