Discovery of Inhibitors of Cell Adhesion Molecule Expression in Human Endothelial Cells. 1. Selective Inhibition of ICAM-1 and E-Selectin Expression

• Published in: Journal of medicinal chemistry 2001-03, Vol.44 (6), p.988-1002
• Main Authors: Stewart, Andrew O, Bhatia, Pramila A, McCarty, Catherine M, Patel, Meena V, Staeger, Michael A, Arendsen, David L, Gunawardana, Indrani W, Melcher, Laura M, Zhu, Gui-Dong, Boyd, Steven A, Fry, Dennis G, Cool, Barbara L, Kifle, Lemma, Lartey, Kraig, Marsh, Kennan C, Kempf-Grote, Anita J, Kilgannon, Patrick, Wisdom, Wendy, Meyer, Joey, Gallatin, W. Michael, Okasinski, Gregory F
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cell Adhesion - drug effects; Cell Line; Depression, Chemical; E-Selectin - genetics; E-Selectin - metabolism; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Enzyme-Linked Immunosorbent Assay; Genes, Reporter; Humans; Intercellular Adhesion Molecule-1 - genetics; Intercellular Adhesion Molecule-1 - metabolism; Luciferases - genetics; Medical sciences; Pharmacology. Drug treatments; Promoter Regions, Genetic; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Pyrimidines - toxicity; Rats; Structure-Activity Relationship; Tumor Necrosis Factor-alpha - pharmacology; Umbilical Veins - cytology; Vascular Cell Adhesion Molecule-1 - genetics; Vascular Cell Adhesion Molecule-1 - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000452m

A critical early event in the inflammatory cascade is the induced expression of cell adhesion molecules on the lumenal surface of vascular endothelial cells. These adhesion molecules include E-selectin, ICAM-1, and VCAM-1, which 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. Pharmaceutical agents which would prevent the induced expression of one or more of the cell adhesion molecules on the endothelium might be expected to provide 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-α (TNFα)-induced expression of E-selectin, ICAM-1, or VCAM-1 on human vascular endothelial cells. Traditional medicinal chemistry methods were applied to this low-micromolar inhibitor, 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 (IC50 = 20 and 25 nM, respectively). The relative position of the nitrogen atom in the thienopyridine isomer was shown to be critical for activity, as was a small amide 2-substituent.