Inhibitory effect of the 4-aminotetrahydroquinoline derivatives, selective chemoattractant receptor-homologous molecule expressed on T helper 2 cell antagonists, on eosinophil migration induced by prostaglandin D2.
Prostaglandin (PG) D2, a major cyclooxygenase metabolite generated from immunologically stimulated mast cells, is known to induce activation and chemotaxis in eosinophils, basophils, and T helper 2 (Th2) lymphocytes via a newly identified PGD2 receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). CRTH2 is hypothesized to play an important role in the outcome of allergic responses. However, the absence of selective CRTH2 antagonists has prevented the elucidation of the role of CRTH2 in pathogenesis of allergic diseases. We now report compounds discovered as selective CRTH2 antagonists, (2R*,4S*)-N-(1-benzoyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenylisobutyramide (K117) and (2R*,4S*)-N-(1-benzoyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenylcyclopropanecarboxamide (K604). K117 and K604 have inhibitory effects on human CRTH2 with Ki values of 5.5 and 11 nM, respectively. The effect of these compounds is CRTH2-specific with no cross-reactivity against 15 other receptors and four arachidonic acid-metabolizing enzymes. K117 and K604 has no effect on the basal Ca2+ level and inhibited the Ca2+ response induced by PGD2 in 293EBNA cells expressing human CRTH2. Also, K117 and K604 inhibit PGD2-induced human eosinophil chemotaxis with IC50 values of 7.8 and 42.2 nM, respectively, but they do not inhibit the CC-chemokine receptor 3 agonist eotaxin-induced chemotaxis. These results indicate that K117 and K604 are highly potent and selective antagonists for human CRTH2. These compounds have possibilities to become useful tools to explore CRTH2 functions in allergic diseases.
Mimura
Hideki
H
Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan. hideki.mimura@kyowa.co.jp
Ikemura
Toshihide
T
Kotera
Osamu
O
Sawada
Masatsugu
M
Tashiro
Satoshi
S
Fuse
Eiichi
E
Ueno
Kimihisa
K
Manabe
Haruhiko
H
Ohshima
Etsuo
E
Karasawa
Akira
A
Miyaji
Hiromasa
H
D002118:Calcium / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000187:drug effects*; D005822:Genetic Vectors; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008024:Ligands; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011457:Prostaglandins D / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects*
D002227:Carbazoles; D016861:Cyclooxygenase Inhibitors; D008024:Ligands; D010975:Platelet Aggregation Inhibitors; D011457:Prostaglandins D; D011804:Quinolines; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013449:Sulfonamides; C063119:ramatroban; D002118:Calcium; D007213:Indomethacin; C036293:prostaglandin D2 receptor