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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

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

Tatsuaki Morokata, Keiko Suzuki, Yohei Masunaga, Katsunari Taguchi, Koichiro Morihira, Ippei Sato, Masahiro Fujii, Satoko Takizawa, Yuichi Torii, Naoyoshi Yamamoto, Masayuki Kaneko, Toshimitsu Yamada, Koichiro Takahashi and Yasuaki Shimizu
Journal of Pharmacology and Experimental Therapeutics April 2006, 317 (1) 244-250; DOI: https://doi.org/10.1124/jpet.105.097048
Tatsuaki Morokata
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Keiko Suzuki
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Yohei Masunaga
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Katsunari Taguchi
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Koichiro Morihira
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Ippei Sato
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Masahiro Fujii
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Satoko Takizawa
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Yuichi Torii
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Naoyoshi Yamamoto
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Masayuki Kaneko
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Toshimitsu Yamada
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Koichiro Takahashi
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Yasuaki Shimizu
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Abstract

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.

Footnotes

  • ABBREVIATIONS: CCR, CC chemokine receptor; CCL, CC chemokine ligand; MCP, monocyte chemotactic protein; [Ca2+]i, intracellular Ca2+ concentration; YM-355179, 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; FBS, fetal bovine serum; CHO, Chinese hamster ovary; HEK, human embryonic kidney; BSA, bovine serum albumin; PBS, phosphate-buffered saline; EDN, eosinophil-derived neurotoxin; GAFS, gated autofluorescence forward scatter; BAL, bronchoalveolar lavage; YM-207086, N-{1-[6-fluoro-2-naphthyl)methyl]piperidin-4-yl}benzamide; IL-5, interleukin 5.

  • doi:10.1124/jpet.105.097048.

    • Received October 12, 2005.
    • Accepted December 7, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 377 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 377, Issue 2
1 May 2021
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

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

Tatsuaki Morokata, Keiko Suzuki, Yohei Masunaga, Katsunari Taguchi, Koichiro Morihira, Ippei Sato, Masahiro Fujii, Satoko Takizawa, Yuichi Torii, Naoyoshi Yamamoto, Masayuki Kaneko, Toshimitsu Yamada, Koichiro Takahashi and Yasuaki Shimizu
Journal of Pharmacology and Experimental Therapeutics April 1, 2006, 317 (1) 244-250; DOI: https://doi.org/10.1124/jpet.105.097048

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

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

Tatsuaki Morokata, Keiko Suzuki, Yohei Masunaga, Katsunari Taguchi, Koichiro Morihira, Ippei Sato, Masahiro Fujii, Satoko Takizawa, Yuichi Torii, Naoyoshi Yamamoto, Masayuki Kaneko, Toshimitsu Yamada, Koichiro Takahashi and Yasuaki Shimizu
Journal of Pharmacology and Experimental Therapeutics April 1, 2006, 317 (1) 244-250; DOI: https://doi.org/10.1124/jpet.105.097048
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