PT - JOURNAL ARTICLE AU - Zhenhua Miao AU - Yu Wang AU - Leleti Manmohan AU - Yu Wang AU - Jarek Kalisiak AU - Jay Powers AU - Matthew Walters AU - Dairaghi Daniel AU - Lisa Seitz AU - Tim Sullivan AU - Tom Schall TI - The CCR4 antagonist CCX6239 for the treatment of allergic airways disease DP - 2013 Sep 01 TA - European Respiratory Journal PG - 3535 VI - 42 IP - Suppl 57 4099 - http://erj.ersjournals.com/content/42/Suppl_57/3535.short 4100 - http://erj.ersjournals.com/content/42/Suppl_57/3535.full SO - Eur Respir J2013 Sep 01; 42 AB - The association of CCR4+ lymphocytes with allergic airway disorders such as rhinitis and asthma has long been known and, as such, there has been considerable interest in developing small molecule antagonists against this target. However, despite the perceived utility, there has been a paucity of CCR4 antagonists advancing into clinical development. CCX6239 is a highly potent, selective and orally bioavailable small molecule antagonist of CCR4 in late stage preclinical development. CCX6239 inhibits both CCL17 and CCL22-induced chemotaxis of human blood lymphocytes with A2 values of 5 and 10 nM, respectively. Importantly, CCX6239 remains potent in the presence of 100% human serum, inhibiting both CCL17 and CCL22-induced chemotaxis of human blood lymphocytes with A2 values of 20 and 26 nM respectively. CCX6239 is highly selective for CCR4, showing no cross-reactivity with other chemokine receptors and no significant activity against the hERG potassium channel or CYP isozymes. CCX6239 also inhibits murine CCR4 in 100% serum with an A2 value of 60 nM. CCX6239 was tested in a murine model of OVA-induced allergic airway inflammation. Doses of CCX6329 that resulted in plasma levels of compound which exceeded the in vitro serum A10 value resulted in a significant reduction in the numbers of leukocytes recovered from the BAL and levels of Th2-associated cytokines. Pharmacokinetic profiles in preclinical species and resultant allometric scaling to humans indicate that a single oral daily dose of CCX6329 would provide serum-adjusted A10 coverage of the receptor in humans. In summary, CCX6239 is a highly potent and selective, orally bioavailable antagonist of CCR4 for potential use in allergic airway inflammation.