RESUMO
A novel series of non-carbohydrate imidazole-based selectin inhibitors has been discovered via high-throughput screening using a P-selectin ELISA-based assay system. The initial lead 1 had an IC(50) of 17 microM in the P-selectin ELISA; this potency was significantly improved via an extensive SAR exploration. One of the current lead compounds (29) has an IC(50) of 300 nM in a P-selectin ELISA; it also has good activity in P- and E-selectin cell adhesion assays and shows efficacy in vivo. These compounds represent a novel series of sLe(X) mimetics with antiinflammatory activity. Their unique profile supports our interest in their further evaluation as drug candidates for the treatment of inflammation. Herein we describe the syntheses, optimization, and SAR of this series of novel potent selectin antagonists.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Imidazóis/síntese química , Imidazóis/farmacologia , Selectinas/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Sítios de Ligação/efeitos dos fármacos , Células CHO , Sequência de Carboidratos , Adesão Celular/efeitos dos fármacos , Cricetinae , Ensaio de Imunoadsorção Enzimática , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Dados de Sequência Molecular , Peritonite/induzido quimicamente , Peritonite/prevenção & controle , TioglicolatosRESUMO
Inhibition of selectin function is expected to aid in the management of diseases characterized by aberrant or chronic inflammation, as in asthma and chronic obstructive pulmonary disease (COPD). Selectin-mediated adhesion of leukocytes to the vascular endothelium is a critical early event in the initiation of the inflammatory response, making it a good target for therapeutic intervention. Many approaches to modulating selectin function have been explored, including competitive inhibition, altering cell-surface expression and inducing shedding/cleavage from the cell surface; however, clinical success has been elusive.