A novel antagonist of prostaglandin D2 blocks the locomotion of eosinophils and basophils.
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) D(2) is considered to be the principal ligand of CRTH2.


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 PGD(2). AZ11665362 was without effect on the PGD(2)-induced inhibition of platelet aggregation. In contrast, AZ11665362 effectively inhibited the in vitro migration of human eosinophils and basophils towards PGD(2). The release of eosinophils from the isolated perfused hind limb of the guinea pig was potently stimulated by PGD(2), 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.
Royer
J F
JF
Institute of Experimental and Clinical Pharmacology, Medical University Graz, Graz, Austria.
Schratl
P
P
Carrillo
J J
JJ
Jupp
R
R
Barker
J
J
Weyman-Jones
C
C
Beri
R
R
Sargent
C
C
Schmidt
J A
JA
Lang-Loidolt
D
D
Heinemann
A
A
D000818:Animals; D001491:Basophils / Q000187:drug effects* / Q000502:physiology; D001853:Bone Marrow; D002227:Carbazoles / Q000037:antagonists & inhibitors*; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D002633:Chemotaxis / Q000187:drug effects* / Q000502:physiology; D006168:Guinea Pigs; D006801:Humans; D010975:Platelet Aggregation Inhibitors; D015230:Prostaglandin D2 / Q000502:physiology*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000037:antagonists & inhibitors*; D018418:Th2 Cells / Q000378:metabolism
D002227:Carbazoles; D010975:Platelet Aggregation Inhibitors; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013449:Sulfonamides; C063119:ramatroban; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor