title: Oral treatment with a novel small molecule alpha 4 integrin antagonist, AJM300, prevents the development of experimental colitis in mice.
abstract: OBJECTIVE
  Inhibition of lymphocyte trafficking by treatment with an anti-α4 integrin antibody has been clinically validated as a therapeutic approach for inflammatory bowel disease (IBD), and the orally effective 'anti-α4 integrin therapy' may be more convenient in clinical practice. The aim of this study was to investigate the pharmacological profile and anti-inflammatory effect of a novel, orally active small molecule α4 integrin antagonist, AJM300.
  
  
  METHODS
  The binding specificity/potency of HCA2969 (the active metabolite of AJM300) were investigated in vitro. The pharmacodynamics for α4 integrin antagonism of AJM300 was investigated in mice. The anti-inflammatory effect of AJM300 fed in a diet and the anti-α4 integrin monoclonal antibody was evaluated in a mouse colitis model induced by transfer of IL-10 deficient T cells.
  
  
  RESULTS
  HCA2969 selectively inhibited the in vitro binding of α4 integrin (α4β7/α4β1) to the cell adhesion molecules. Oral treatment with AJM300 dose-dependently inhibited lymphocyte homing to Peyer's patches and increased the peripheral lymphocyte count in the same dose range. AJM300 dose-dependently prevented the development of experimental colitis in mice. A significant inhibition of colon weight increase was accompanied by inhibition of T-cell infiltration into the lamina propria of colon. The maximum efficacy of AJM300 (1% diet) was comparable to that achieved by the saturated α4 integrin blockade with antibody.
  
  
  CONCLUSIONS
  Oral treatment with the selective small molecule α4 integrin antagonist (AJM300) prevented the development of colitis and its efficacy was comparable to that of the anti-α4 integrin antibody.
authors.affiliation: Ajinomoto Pharmaceuticals Co., Ltd, Kawasaki, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Sugiura
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kageyama
authors.forename: Ayatoshi
authors.initials: A
authors.lastname: Andou
authors.forename: Tomoko
authors.initials: T
authors.lastname: Miyazawa
authors.forename: Chieko
authors.initials: C
authors.lastname: Ejima
authors.forename: Akira
authors.initials: A
authors.lastname: Nakayama
authors.forename: Taeko
authors.initials: T
authors.lastname: Dohi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Eda
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001707:Biopsy, Needle; D015815:Cell Adhesion Molecules / Q000187:drug effects; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000473:pathology* / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D007150:Immunohistochemistry; D039441:Integrin alpha4 / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D052999:Quinazolinones / Q000008:administration & dosage*; D011897:Random Allocation; D012016:Reference Values
chemical_list: C000588820:AJM300; D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D052999:Quinazolinones; D039441:Integrin alpha4; D010649:Phenylalanine
keywords: 4′,6-diamidino-2-phenylindole; AJM300; AJM300M1; CTRL; DAPI; HEK; IBD; ICAM-1; IL-10; Inflammatory bowel disease; Lymphocyte homing; MAdCAM-1; Oral drug; PBS; PD; PK; SCID; VCAM-1; a special formulation containing AJM300 at approximately 43% and excipients: AJM300M1 preparation; control; human embryonic kidney; inflammatory bowel disease; intercellular adhesion molecule-1; interleukin-10; mucosal addressin cell adhesion molecule-1; orally active small molecule α4 integrin antagonist; pharmacodynamics; pharmacokinetics; phosphate-buffered saline; severe combined immuno-defficient; vascular cell adhesion molecule-1; α4 Integrin antagonist