Received for publication December 7, 2004.
Revised March 24, 2005.
Accepted for publication March 25, 2005.

Inhibitory effect of the 4-aminotetrahydroquinoline derivatives, selective CRTH2 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 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 nM and 11 nM, respectively. The effect of these compounds is CRTH2-specific with no cross-reactivity against 15 other receptors and 4 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 nM and 42.2 nM, respectively, but do not inhibit the CCR3 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.

Key words: Allergy, Antagonist, Prostaglandin D2, Receptors, T-lymphocytes, eosinophils

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