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Bioorg Med Chem Lett. 2010 Sep 1;20(17):5269-73. doi: 10.1016/j.bmcl.2010.06.145. Epub 2010 Jul 23.

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

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1
Sunesis Pharmaceuticals, Inc., 395 Oyster Point Blvd., South San Francisco, CA 94080, USA. mzhong@presidiopharma.com

Abstract

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.

PMID:
20655213
DOI:
10.1016/j.bmcl.2010.06.145
[Indexed for MEDLINE]
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