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

Biochem Biophys Res Commun. 2006 Jan 27;339(4):1217-23. doi: 10.1016/j.bbrc.2005.11.141. Epub 2005 Dec 5.

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.

MeSH terms

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

Substances

  • 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