RESUMO
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.
Assuntos
Antígeno-1 Associado à Função Linfocitária/metabolismo , Compostos de Espiro/síntese química , Tiofenos/síntese química , Animais , Adesão Celular/efeitos dos fármacos , Cristalografia por Raios X , Cães , Rejeição de Enxerto/prevenção & controle , Humanos , Antígeno-1 Associado à Função Linfocitária/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/farmacocinética , Tiofenos/farmacologia , Transplante HomólogoRESUMO
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.