In vitro and in vivo characterization of a novel CCR3 antagonist, YM-344031.

Abstract

Eosinophils play a prominent proinflammatory role in a broad range of diseases, including atopic dermatitis and asthma. Eotaxin-1 and its receptor CCR3 are implicated in the recruitment of eosinophils from blood into inflammatory tissues, therefore inhibition of Eotaxin-1/CCR3 interaction may have therapeutic potential for allergic inflammation with eosinophil infiltration. YM-344031, a novel and selective small molecule CCR3 antagonist, potently inhibited ligand binding (IC(50)=3.0nM), ligand-induced Ca(2+) flux (IC(50)=5.4nM), and the chemotaxis of human CCR3-expressing cells (IC(50)=19.9nM). YM-344031 (1-10mg/kg) orally administered to cynomolgus monkeys significantly inhibited Eotaxin-1-induced eosinophil shape change in whole blood. Additionally, orally administered YM-344031 (100mg/kg) prevented both immediate- and late-phase allergic skin reactions in a mouse allergy model. YM-344031 therefore has potential as a novel and orally available compound for the treatment of allergic inflammation, such as atopic dermatitis and asthma.

• Authors: Keiko Suzuki, Tatsuaki Morokata, Koichiro Morihira, Ippei Sato, Satoko Takizawa, Masayuki Kaneko, Koichiro Takahashi, Yasuaki Shimizu
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 339 Issue 4 Pg. 1217-23 (Jan 27 2006) ISSN: 0006-291X [Print] United States
• PMID: 16343433 (Publication Type: Journal Article)

Chemical References

• Amides
• CCR3 protein, human
• Ccr3 protein, mouse
• N-(1-((6-fluoro-2-naphthyl)methyl)pyrrolidin-3-yl)-2-(1-((3-methyl-1-oxidopyridin-2-yl)carbonyl)piperidin-4-ylidene)acetamide
• Pyridinium Compounds
• Receptors, CCR3
• Receptors, Chemokine

Topics

• Administration, Oral
• Amides (administration & dosage)
• Animals
• Cells, Cultured
• Dermatitis (immunology, pathology, prevention & control)
• Dose-Response Relationship, Drug
• Humans
• Macaca fascicularis
• Male
• Mice
• Mice, Inbred BALB C
• Pyridinium Compounds (administration & dosage)
• Receptors, CCR3
• Receptors, Chemokine (agonists, immunology)
• Spleen (drug effects, immunology)
• Treatment Outcome