Inhibition of E-selectin-, ICAM-1-, and VCAM-1-mediated cell adhesion by benzo[b]thiophene-, benzofuran-, indole-, and naphthalene-2-carboxamides: identification of PD 144795 as an antiinflammatory agent.
It was previously reported that 3-alkoxybenzo[b]thiophene-2-carboxamides exemplified by 1, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide, decreased the adherence of neutrophils to activated endothelial cells by inhibiting the upregulation of the adhesion molecules E-selectin and ICAM-1 on the surface of the endothelium. This finding is extended here to a series of 3-thiobenzo[b]thiophene-2-carboxamides and also heterocyclic analogs of 1, including benzofurans, indoles, and napthalenes. The compounds that inhibited the expression of E-selectin and ICAM-1 had the same effect on the expression of VCAM-1. PD 144795, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide 1-oxide (44), the sulfoxide analog of 1, was orally active in several models of inflammation. The in vitro and in vivo activity of PD 144795 resided predominately in the S-enantiomer.
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000138:chemical synthesis / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects*; D015815:Cell Adhesion Molecules / Q000494:pharmacology*; D002478:Cells, Cultured; D019040:E-Selectin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009281:Naphthalenes / Q000138:chemical synthesis / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000494:pharmacology
D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001572:Benzofurans; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D007211:Indoles; D009281:Naphthalenes; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C095579:PD 144795