Inhibitory effects of an orally active small molecule alpha4beta1/alpha4beta7 integrin antagonist, TR-728, on DSS-induced experimental colitis in mice and spontaneous colitis in HLA-B27 transgenic rats

Background & Aims: The successful treatment of inflammatory bowel disease (IBD) in humans with anti-alpha4 or anti-alpha4/beta7 integrin antibody has emphasized the clinical importance of alpha4 integrins that mediate leukocyte migration; however an increased risk for a rare brain disease, progressive multifocal leukoencephalopathy (PML) has been suggested for the anti-alpha4 integrin antibody. TR-728 is a novel orally active small molecule alpha4beta1/alpha4beta7 integrin antagonist and has different properties from the antibody, such as gut-dominant distribution and selectivity for the acive form of alpha4beta1. The aim of this study was to evaluate the effect of TR-728 on two chronic colitis models resembling ulcerative colitis (UC) which is one of major types of IBD.