Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 and αLβ2, is a member of the β2-integrin family found on lymphocytes and other leukocytes. The main ligand of LFA-1 is ICAM-1, and the LFA-1/ICAM interaction stimulates signaling pathways that influence T cell differentiation. It has two subunits designated as the α subunit and β subunit. The amino-terminal region of the CD11a (αL) subunit of LFA-1 contains an inserted domain (termed the I-domain). Specifically, changes in I-domain allosteric site (IDAS) lead to high-affinity LFA-1/ICAM-1 interactions. In autoimmune or inflammatory diseases, there is increased expression of LFA-1 and/or its counterligand, ICAM-1. Suzanne J Suchard et al. demonstrated that LFA-1 small-molecule antagonists have the ability to improve the disease in rheumatoid arthritis.
BMS-587101 is a potent and orally active LFA-1 antagonist. In vitro, BMS-587101 effectively inhibits LFA-1 mediated T-cell proliferation in human HUVEC cells. Moreover, BMS-587101 also inhibits the adhesion of mouse T cells to the mouse brain microvascular endothelial cell line. In addition, it can block the proliferation of human T cells in mixed lymphocyte reaction (MLR) assay. And this compound also inhibits the production of Th1 cytokines in response to staphylococcal enterotoxin B (SEB)-induced T cell activation. In vivo, in the mouse ovalbumin-induced lung inflammation model, BMS-587101 treatment significantly inhibits eosinophil accumulation. Similarly, BMS-587101 has the capacity for disease modification in antibody-induced arthritis and collagen-induced arthritis. Besides, in heart-to-ear nonvascularized allograft transplant model, the combination of BMS-587101 with CTLA-4Ig increased graft survival substantially.
In general, BMS-587101 is a potent and orally active LFA-1 antagonist, with efficacy in in vivo models of inflammation.