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

The discovery of a novel series of tetrahydroisoquinoline (THIQ) derivatives as potent and orally bioavailable LFA-1/ICAM-1 antagonists is described. This letter describes the discovery of a novel series of tetrahydroisoquinoline (THIQ)-derived small molecules that potently inhibit both human T-cell...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 20; no. 17; pp. 5269 - 5273
Main Authors:	Zhong, Min, Shen, Wang, Barr, Kenneth J., Arbitrario, Jennifer P., Arkin, Michelle R., Bui, Minna, Chen, Teresa, Cunningham, Brian C., Evanchik, Marc J., Hanan, Emily J., Hoch, Ute, Huen, Karen, Hyde, Jennifer, Kumer, Jeffery L., Lac, Teresa, Lawrence, Chris E., Martell, Jose R., Oslob, Johan D., Paulvannan, Kumar, Prabhu, Saileta, Silverman, Jeffrey A., Wright, Jasmin, Yu, Chul H., Zhu, Jiang, Flanagan, W. Mike
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ltd 01-09-2010 Elsevier
Subjects:	Animals Antagonist Biological and medical sciences Biological Availability Drug Discovery Humans Immunomodulators Intercellular adhesion molecule-1 (ICAM-1) Intercellular Adhesion Molecule-1 - drug effects Leukocyte function-associated antigen-1 (LFA-1) Lymphocyte Function-Associated Antigen-1 - drug effects Medical sciences Pharmacology. Drug treatments Tetrahydroisoquinoline (THIQ) derivative Tetrahydroisoquinolines - administration & dosage Tetrahydroisoquinolines - pharmacokinetics Tetrahydroisoquinolines - pharmacology Tetrahydroisoquinoline (THIQ) derivative Intercellular adhesion molecule-1 (ICAM-1) Antagonist Leukocyte function-associated antigen-1 (LFA-1) Rat Lymphocyte function associated antigen 1 Thiophene derivatives Leukocyte function-associated antigen-1 Chlorine Organic compounds Isoquinoline derivatives Intercellular adhesion molecule 1 LFA-1 Rodentia Cell adhesion molecule Oral administration Bioavailability Adhesion In vitro Biological activity In vivo Vertebrata Mammalia Mouse Aminoacid Animal Benzofuran derivatives β2 integrin Pharmacokinetics
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Summary:	The discovery of a novel series of tetrahydroisoquinoline (THIQ) derivatives as potent and orally bioavailable LFA-1/ICAM-1 antagonists is described. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.06.145