Oral treatment with a novel small molecule alpha 4 integrin antagonist, AJM300, prevents the development of experimental colitis in mice.
J Crohns Colitis
; 7(11): e533-42, 2013 Dec.
Article
em En
| MEDLINE
| ID: mdl-23623333
ABSTRACT
BACKGROUND AND AIMS:
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 (α4ß7/α4ß1) 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.Palavras-chave
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
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Fenilalanina
/
Colite Ulcerativa
/
Integrina alfa4
/
Quinazolinonas
/
Anticorpos Monoclonais
Limite:
Animals
Idioma:
En
Revista:
J Crohns Colitis
Assunto da revista:
GASTROENTEROLOGIA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Japão