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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 317; no. 1; pp. 244 - 250
• Main Authors: Morokata, Tatsuaki, Suzuki, Keiko, Masunaga, Yohei, Taguchi, Katsunari, Morihira, Koichiro, Sato, Ippei, Fujii, Masahiro, Takizawa, Satoko, Torii, Yuichi, Yamamoto, Naoyoshi, Kaneko, Masayuki, Yamada, Toshimitsu, Takahashi, Koichiro, Shimizu, Yasuaki
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.04.2006
• Subjects: Administration, Oral; Animals; Binding, Competitive; Bronchoalveolar Lavage Fluid - cytology; Calcium - metabolism; Cell Degranulation - drug effects; Cell Line, Tumor; Chemokine CCL11; Chemokines, CC - metabolism; Chemotaxis, Leukocyte - drug effects; Cloning, Molecular; Eosinophils - drug effects; Eosinophils - physiology; Epoxy Compounds - administration & dosage; Epoxy Compounds - pharmacology; Humans; Injections, Intravenous; Ligands; Lung - drug effects; Macaca fascicularis; Mice; Molecular Structure; Morphinans - administration & dosage; Morphinans - pharmacology; Receptors, CCR3; Receptors, Chemokine - antagonists & inhibitors
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.105.097048

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 -{(3 R )-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 IC 50 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 Ca 2+ influx, chemotaxis, and eosinophil degranulation with IC 50 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 Ca 2+ 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.