title: Discovery of inhibitors of cell adhesion molecule expression in human endothelial cells. 1. Selective inhibition of ICAM-1 and E-selectin expression.
abstract: 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-alpha (TNFalpha)-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 (IC(50) = 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.
authors: Abbott Laboratories, Pharmaceutical Products Division, Metabolic Diseases Research, Department 04MJ, Building AP10, 100 Abbott Park Road, Abbott Park, Illinois 60064-3500, USA.
authors: A O
authors: AO
authors: Stewart
authors: P A
authors: PA
authors: Bhatia
authors: C M
authors: CM
authors: McCarty
authors: M V
authors: MV
authors: Patel
authors: M A
authors: MA
authors: Staeger
authors: D L
authors: DL
authors: Arendsen
authors: I W
authors: IW
authors: Gunawardana
authors: L M
authors: LM
authors: Melcher
authors: G D
authors: GD
authors: Zhu
authors: S A
authors: SA
authors: Boyd
authors: D G
authors: DG
authors: Fry
authors: B L
authors: BL
authors: Cool
authors: L
authors: L
authors: Kifle
authors: K
authors: K
authors: Lartey
authors: K C
authors: KC
authors: Marsh
authors: A J
authors: AJ
authors: Kempf-Grote
authors: P
authors: P
authors: Kilgannon
authors: W
authors: W
authors: Wisdom
authors: J
authors: J
authors: Meyer
authors: W M
authors: WM
authors: Gallatin
authors: G F
authors: GF
authors: Okasinski
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D003864:Depression, Chemical; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D017930:Genes, Reporter; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D019040:E-Selectin; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D008156:Luciferases