ABSTRACT
LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.
Subject(s)
Lymphocyte Function-Associated Antigen-1/metabolism , Spiro Compounds/chemical synthesis , Thiophenes/chemical synthesis , Animals , Cell Adhesion/drug effects , Crystallography, X-Ray , Dogs , Graft Rejection/prevention & control , Humans , Lymphocyte Function-Associated Antigen-1/chemistry , Mice , Models, Molecular , Molecular Structure , Pneumonia/drug therapy , Pneumonia/immunology , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity Relationship , Thiophenes/pharmacokinetics , Thiophenes/pharmacology , Transplantation, HomologousABSTRACT
LFA-1 (leukocyte function-associated antigen-1), is a member of the beta(2)-integrin family and is expressed on all leukocytes. The LFA-1/ICAM interaction promotes tight adhesion between activated leukocytes and the endothelium, as well as between T cells and antigen-presenting cells. Evidence from both animal models and clinical trials provides support for LFA-1 as a target in several different inflammatory diseases. This paper describes the de novo design, synthesis and in vitro activity of LFA-1 antagonists based on a bicyclic[5.5]hydantoin scaffold.
