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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.
J Pharmacol Exp Ther. 2005 Jul; 314(1):244-51.JP

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+Show Affiliations

Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan. hideki.mimura@kyowa.co.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15798001

Citation

Mimura, Hideki, et al. "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." The Journal of Pharmacology and Experimental Therapeutics, vol. 314, no. 1, 2005, pp. 244-51.
Mimura H, Ikemura T, Kotera O, et al. 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. J Pharmacol Exp Ther. 2005;314(1):244-51.
Mimura, H., Ikemura, T., Kotera, O., Sawada, M., Tashiro, S., Fuse, E., Ueno, K., Manabe, H., Ohshima, E., Karasawa, A., & Miyaji, H. (2005). 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. The Journal of Pharmacology and Experimental Therapeutics, 314(1), 244-51.
Mimura H, et al. 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. J Pharmacol Exp Ther. 2005;314(1):244-51. PubMed PMID: 15798001.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Mimura,Hideki, AU - Ikemura,Toshihide, AU - Kotera,Osamu, AU - Sawada,Masatsugu, AU - Tashiro,Satoshi, AU - Fuse,Eiichi, AU - Ueno,Kimihisa, AU - Manabe,Haruhiko, AU - Ohshima,Etsuo, AU - Karasawa,Akira, AU - Miyaji,Hiromasa, Y1 - 2005/03/29/ PY - 2005/3/31/pubmed PY - 2005/8/27/medline PY - 2005/3/31/entrez SP - 244 EP - 51 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 314 IS - 1 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/15798001/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_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15798001 DB - PRIME DP - Unbound Medicine ER -