title: An LFA-1 (alphaLbeta2) small-molecule antagonist reduces inflammation and joint destruction in murine models of arthritis.
abstract: LFA-1 appears to play a central role in normal immune responses to foreign Ags. In autoimmune or inflammatory diseases, there is increased expression of LFA-1 and/or its counterligand, ICAM-1. Others have demonstrated that the targeted disruption of LFA-1:ICAM interactions, either by gene deletion or Ab treatment in mice, results in reduced leukocyte trafficking, inflammatory responses, and inhibition of inflammatory arthritis in the K/BxN serum transfer model. However, there has been little success in finding a small-molecule LFA-1 antagonist that can similarly impact rodent models of arthritis. In this paper, we present the first reported example of an LFA-1 small-molecule antagonist, BMS-587101, that is efficacious in preclinical disease models. In vitro, BMS-587101 inhibited LFA-1-mediated adhesion of T cells to endothelial cells, T cell proliferation, and Th1 cytokine production. Because BMS-587101 exhibits in vitro potency, cross-reactivity, and oral bioavailability in rodents, we evaluated the impact of oral administration of this compound in two different models of arthritis: Ab-induced arthritis and collagen-induced arthritis. Significant impact of BMS-587101 on clinical score in both models was observed, with inhibition comparable or better than anti-mouse LFA-1 Ab. In addition, BMS-587101 significantly reduced cytokine mRNA levels in the joints of Ab-induced arthritis animals as compared with those receiving vehicle alone. In paws taken from the collagen-induced arthritis study, the bones of vehicle-treated mice had extensive inflammation and bone destruction, whereas treatment with BMS-587101 resulted in marked protection. These findings support the potential use of an LFA-1 small-molecule antagonist in rheumatoid arthritis, with the capacity for disease modification.
authors.affiliation: Department of Immunology and Inflammation Drug Discovery, Bristol-Myers Squibb, Princeton, NJ 08543, USA. suzanne.suchard@bms.com
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Suchard
authors.forename: Dawn K
authors.initials: DK
authors.lastname: Stetsko
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Davis
authors.forename: Stacey
authors.initials: S
authors.lastname: Skala
authors.forename: Dominique
authors.initials: D
authors.lastname: Potin
authors.forename: Michele
authors.initials: M
authors.lastname: Launay
authors.forename: T G Murali
authors.initials: TG
authors.lastname: Dhar
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: Vojkan
authors.initials: V
authors.lastname: Susulic
authors.forename: David J
authors.initials: DJ
authors.lastname: Shuster
authors.forename: Kim W
authors.initials: KW
authors.lastname: McIntyre
authors.forename: Murray
authors.initials: M
authors.lastname: McKinnon
authors.forename: Luisa
authors.initials: L
authors.lastname: Salter-Cid
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D007959:Lymphocyte Culture Test, Mixed; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D013141:Spiro Compounds / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: C517055:5-(9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro(4,4)non-7-ylmethyl)-3-thiophenecarboxylic acid; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D016169:Lymphocyte Function-Associated Antigen-1; D013141:Spiro Compounds; D013876:Thiophenes