title: 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.
abstract: 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.
authors.affiliation: Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan. hideki.mimura@kyowa.co.jp
authors.forename: Hideki
authors.initials: H
authors.lastname: Mimura
authors.forename: Toshihide
authors.initials: T
authors.lastname: Ikemura
authors.forename: Osamu
authors.initials: O
authors.lastname: Kotera
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Sawada
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tashiro
authors.forename: Eiichi
authors.initials: E
authors.lastname: Fuse
authors.forename: Kimihisa
authors.initials: K
authors.lastname: Ueno
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Manabe
authors.forename: Etsuo
authors.initials: E
authors.lastname: Ohshima
authors.forename: Akira
authors.initials: A
authors.lastname: Karasawa
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Miyaji
mesh_terms: 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*
chemical_list: 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