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INFLAMMATION AND IMMUNOPHARMACOLOGY

A Novel, Selective, and Orally Available Antagonist for CC Chemokine Receptor 3

Inflammation Research Pharmacology Laboratory (T.M., K.S., Y.M., K.T., T.Y., K.T., Y.S.), Medicinal Chemistry Research II Chemistry Laboratory (K.M., I.S.), and Discovery Metabolism Research Analysis and Metabolism Laboratory (M.F.), Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Japan; and Pharmaceutical Research Laboratories (S.T., Y.T., N.Y., M.K.), Toray Industries, Inc., Kamakura, Japan

CC chemokine ligand 11 (CCL11/eotaxin) and other CC chemokine receptor 3 (CCR3) ligands (CCL24/eotaxin-2, CCL26/eotaxin-3, CCL13/monocyte chemotactic protein-4, etc.) play important roles in the chemotaxis and activation of eosinophils and other CCR3-expressing cells (basophils, mast cells, and CD4⁺ T helper 2 cells) in allergic inflammation incidents, including asthma and rhinitis. A newly synthesized compound, N-{(3R)-1-[(6-fluoro-2-naphthyl)methyl]pyrrolidin-3-yl}-2-{1-[(5-hydroxy-3-methylpyridin-2-yl)carbonyl]piperidin-4-ylidene}-acetamide hemifumarate (YM-355179), inhibited the binding of CCL11 and CCL5/regulated on activation normal T cell expressed and secreted to CCR3-expressing B300-19 cells with IC₅₀ values of 7.6 and 24 nM, respectively. In contrast, YM-355179 did not affect the binding of CCL5 to CCR1 or CCR5. In functional assays, YM-355179 inhibited CCL11-induced, intracellular Ca²⁺ influx, chemotaxis, and eosinophil degranulation with IC₅₀ values of 8.0, 24, and 29 nM, respectively. YM-355179 did not, however, affect any CC chemokine receptor (CCR1, CCR2, CCR4, or CCR5)-mediated Ca²⁺ influx signals. Furthermore, oral administration of YM-355179 (1 mg/kg) inhibited CCL11-induced shape change of whole blood eosinophils in cynomolgus monkeys. Intravenous injection of YM-355179 (1 mg/kg) also inhibited eosinophil infiltration into airways of cynomolgus monkeys after segmental bronchoprovocation with CCL11. These results indicate that YM-355179 is a novel, selective, and orally available CCR3 antagonist with therapeutic potential for treating eosinophil-related allergic inflammatory diseases.

Address correspondence to: Tatsuaki Morokata, Department of Immunology, Pharmacology Research Laboratories, Institute for Drug Discovery Research, Astellas Pharma Inc., 1-6, Kashima 2-Chome, Yodogawa-ku, Osaka 532-8514, Japan. E-mail: tatsuaki.morokata{at}jp.astellas.com

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