title: 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 [(125) I]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 IC(50) 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.
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan. nakagami.yasuhiro.y4@daiichisankyo.co.jp
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakagami
authors.forename: Kayo
authors.initials: K
authors.lastname: Kawashima
authors.forename: Maki
authors.initials: M
authors.lastname: Etori
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yonekubo
authors.forename: Chie
authors.initials: C
authors.lastname: Suzuki
authors.forename: Takaaki
authors.initials: T
authors.lastname: Jojima
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kuribayashi
authors.forename: Futoshi
authors.initials: F
authors.lastname: Nara
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamashita
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002634:Chemotaxis, Leukocyte; D004431:Ear, External / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D004487:Edema / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010047:Ovalbumin / Q000276:immunology; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012772:Shock, Septic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D001549:Benzamides; D008070:Lipopolysaccharides; D009025:Morpholines; C556386:RS-1269; D054398:Receptors, CCR4; D014409:Tumor Necrosis Factor-alpha; D010047:Ovalbumin