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

• Published in: Journal of medicinal chemistry Vol. 38; no. 22; pp. 4597 - 4614
• Main Authors: Boschelli, Diane H, Kramer, James B, Khatana, Sonya S, Sorenson, Roderick J, Connor, David T, Ferin, Mark A, Wright, Clifford D, Lesch, Mark E, Imre, Kathleen
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.10.1995
• Subjects: Administration, Oral; Amides - chemical synthesis; Amides - pharmacology; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Benzofurans - chemical synthesis; Benzofurans - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cell Adhesion - drug effects; Cell Adhesion Molecules - pharmacology; Cells, Cultured; E-Selectin - pharmacology; Endothelium, Vascular - cytology; Humans; Indoles - chemical synthesis; Indoles - pharmacology; Intercellular Adhesion Molecule-1 - pharmacology; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Naphthalenes - chemical synthesis; Naphthalenes - pharmacology; Neutrophils - cytology; Pharmacology. Drug treatments; Thiophenes - chemical synthesis; Thiophenes - pharmacology; Tumor Necrosis Factor-alpha - pharmacology; Vascular Cell Adhesion Molecule-1 - pharmacology; Endothelial cell; Rat; Structure activity relation; Enantiomer; Pleurisy; Bicyclic compound; Aromatic compound; Chemical synthesis; Peritonitis; Ether; Intercellular adhesion molecule 1; Respiratory disease; Rodentia; Antiinflammatory agent; Oral administration; Adhesion; In vitro; In vivo; Vertebrata; Chemotherapy; Sulfur heterocycle; Experimental disease; Mammalia; Treatment; Mouse; Abdominal disease; Animal; Phenols; Sulfoxide; Carboxamide; S configuration; Inhibitor; Neutrophil
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00022a026

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.