Discovery of tetrahydroisoquinoline (THIQ) derivatives as potent and orally bioavailable LFA-1/ICAM-1 antagonists

✍ Scribed by Min Zhong; Wang Shen; Kenneth J. Barr; Jennifer P. Arbitrario; Michelle R. Arkin; Minna Bui; Teresa Chen; Brian C. Cunningham; Marc J. Evanchik; Emily J. Hanan; Ute Hoch; Karen Huen; Jennifer Hyde; Jeffery L. Kumer; Teresa Lac; Chris E. Lawrence; Jose R. Martell; Johan D. Oslob; Kumar Paulvannan; Saileta Prabhu; Jeffrey A. Silverman; Jasmin Wright; Chul H. Yu; Jiang Zhu; W. Mike Flanagan

• Book ID: 104004610
• Publisher: Elsevier Science
• Year: 2010
• Tongue: English
• Weight: 600 KB
• Volume: 20
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2010.06.145

✦ Synopsis

This letter describes the discovery of a novel series of tetrahydroisoquinoline (THIQ)-derived small molecules that potently inhibit both human T-cell migration and super-antigen induced T-cell activation through disruption of the binding of integrin LFA-1 to its receptor, ICAM-1. In addition to excellent in vitro potency, 6q shows good pharmacokinetic properties and its ethyl ester (6t) demonstrates good oral bioavailability in both mouse and rat. Either intravenous administration of 6q or oral administration of its ethyl ester (6t) produced a significant reduction of neutrophil migration in a thioglycollate-induced murine peritonitis model.