Discovery of inhibitors of cell adhesion molecule expression in human endothelial cells. 1. Selective inhibition of ICAM-1 and E-selectin expression

A critical early event in the inflammatory cascade is the induced expressio n of cell adhesion molecules on the lumenal surface of vascular endothelial cells. These adhesion molecules include E-selectin, ICAM-1, and VCAM-1, wh ich serve to recruit circulating leukocytes to the site of the inflammation . These adhesive interactions allow the leukocytes to firmly adhere to and cross the vascular endothelium and migrate to the site of tissue injury. Ph armaceutical agents which would prevent the induced expression of one or mo re of the cell adhesion molecules on the endothelium might be expected to p rovide a novel mechanism to attenuate the inflammatory responses associated with chronic inflammatory diseases. A thieno[2,3-d] pyrimidine, A-155918, was identified from a whole-cell high-throughput assay for compounds which inhibited the tumor necrosis factor-alpha (TNF alpha)-induced expression of E-selectin, ICAM-1, or VCAM-1 on human vascular endothelial cells. Traditi onal medicinal chemistry methods were applied to this low-micromolar inhibi tor, resulting in the 2,4-disubstituted thieno [2,3-c]pyridine A-205804, a potent and selective lead inhibitor of E-selectin and ICAM-1 expression (IC 50 = 20 and 25 nM, respectively). The relative position of the nitrogen ato m in the thienopyridine isomer was shown to be critical for activity, as wa s a small amide 2-substituent.