Development of potent non-carbohydrate imidazole-based small molecule selectin inhibitors with antiinflammatory activity

A novel series of non-carbohydrate imidazole-based selectin inhibitors has been discovered via high-throughput screening using a P-selectin ELISA-base d assay system. The initial lead 1 had an IC50 of 17 muM in the P-selectin ELISA; this potency was significantly improved via an extensive SAR explora tion. One of the current lead compounds (29) has an IC50 of 300 nM in a P-s electin ELISA; it also has good activity in P- and E-selectin cell adhesion assays and shows efficacy in vivo. These compounds represent a novel serie s of sLe(X) mimetics with antiinflammatory activity. Their unique profile s upports 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.