A novel antagonist of prostaglandin D2 blocks the locomotion of eosinophils and basophils
Article first published online: 18 AUG 2008
© 2008 The Authors. Journal Compilation © 2008 Blackwell Publishing Ltd
European Journal of Clinical Investigation
Volume 38, Issue 9, pages 663–671, September 2008
How to Cite
Royer, J. F., Schratl, P., Carrillo, J. J., Jupp, R., Barker, J., Weyman-Jones, C., Beri, R., Sargent, C., Schmidt, J. A., Lang-Loidolt, D. and Heinemann, A. (2008), A novel antagonist of prostaglandin D2 blocks the locomotion of eosinophils and basophils. European Journal of Clinical Investigation, 38: 663–671. doi: 10.1111/j.1365-2362.2008.01989.x
- Issue published online: 18 AUG 2008
- Article first published online: 18 AUG 2008
- Received 27 December 2007; accepted 3 June 2008
- bone marrow;
Background Chemoattractant receptor homologous molecule of Th2 cells (CRTH2) has been shown to mediate the chemotaxis of eosinophils, basophils and Th2-type T lymphocytes. The major mast cell product prostaglandin (PG) D2 is considered to be the principal ligand of CRTH2.
Materials and methods We developed a novel CRTH2 antagonist, AZ11665362 [2,5-dimethyl-3-(8-methylquinolin-4-yl)-1H-indole-1-yl]acetic acid, and characterized its efficacy in binding assay in HEK293 cells, eosinophil and basophil shape change assay and migration assay, platelet aggregation and eosinophil release from guinea pig bone marrow. The effects were compared with ramatroban, the sole CRTH2 antagonist clinically available to date.
Results AZ11665362 bound with high affinity to human and guinea pig CRTH2 expressed in HEK293 cells and antagonized eosinophil and basophil shape change responses to PGD2. AZ11665362 was without effect on the PGD2-induced inhibition of platelet aggregation. In contrast, AZ11665362 effectively inhibited the in vitro migration of human eosinophils and basophils towards PGD2. The release of eosinophils from the isolated perfused hind limb of the guinea pig was potently stimulated by PGD2, and this effect was prevented by AZ11665362. In all assays tested, AZ11665362 was at least 10 times more potent than ramatroban.
Conclusions AZ11665362 is a potent CRTH2 antagonist that is capable of blocking the migration of eosinophils and basophils, and the rapid mobilization of eosinophils from bone marrow. AZ11665362 might hence be useful for the treatment of allergic diseases.