A Novel CC Chemokine Receptor 4 Antagonist RS‐1269 Inhibits Ovalbumin‐Induced Ear Swelling and Lipopolysaccharide‐Induced Endotoxic Shock in Mice

Abstract: There is growing evidence that chemokines recruit leukocytes in allergic, inflammatory and immune responses. CC chemokine receptor 4 (CCR4) is implicated as a preferential marker for T helper 2 cells, and the cells selectively respond to CC chemokine ligand 17 (CCL17) and CCL22. We searched for compounds having a profile as a CCR4 antagonist from an in‐house library and have previously reported that 3‐{2‐[(2R)‐2‐phenyl‐4‐(4‐pyridin‐4‐ylbenzyl)morpholin‐2‐yl]ethyl}quinazoline‐2,4(1H,3H)‐dione (named RS‐1154) was capable of significantly inhibiting the binding of [¹²⁵I]CCL17 to human CCR4‐expressing CHO cells. From further synthesis of its derivatives, we newly focused on 3‐(isobutyrylamino)‐N‐{2‐[(2R)‐2‐phenyl‐4‐(4‐pyridin‐4‐ylbenzyl)morpholin‐2‐yl]ethyl}benzamide (RS‐1269), which showed potency comparable to RS‐1154 in inhibiting CCL17‐induced migration of DO11.10 mice‐derived T helper 2 cells with an IC₅₀ value of 5.5 nM in vitro. We then investigated the pharmacological effects of RS‐1269 on ovalbumin‐induced ear swelling and lipopolysaccharide‐induced endotoxic shock in mice. The ear thickness was significantly decreased by oral administration of RS‐1269 at the dose of 30 mg/kg. Treatment with lipopolysaccharide significantly increased the serum level of tumour necrosis factor‐α. Compared with an anti‐CCL17 antibody, RS‐1269 significantly inhibited the production at the dose of 100 mg/kg. These results raise the possibility that RS‐1269 or one of its derivatives has potential to serve as a prototype compound to develop therapeutic agents for atopic dermatitis and inflammatory diseases.