Literature DB >> 24900456

Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye.

Min Zhong1, Thomas R Gadek2, Minna Bui1, Wang Shen1, John Burnier2, Kenneth J Barr1, Emily J Hanan1, Johan D Oslob1, Chul H Yu1, Jiang Zhu1, Michelle R Arkin1, Marc J Evanchik1, W Mike Flanagan1, Ute Hoch1, Jennifer Hyde1, Saileta Prabhu1, Jeffrey A Silverman1, Jasmin Wright1.   

Abstract

LFA-1/ICAM-1 interaction is essential in support of inflammatory and specific T-cell regulated immune responses by mediating cell adhesion, leukocyte extravasation, migration, antigen presentation, formation of immunological synapse, and augmentation of T-cell receptor signaling. The increase of ICAM-1 expression levels in conjunctival epithelial cells and acinar cells was observed in animal models and patients diagnosed with dry eye. Therefore, it has been hypothesized that small molecule LFA-1/ICAM-1 antagonists could be an effective topical treatment for dry eye. In this letter, we describe the discovery of a potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonist (SAR 1118) and its development as an ophthalmic solution for treating dry eye.

Entities:  

Keywords:  LFA-1/ICAM-1 antagonist; SAR 1118; dry eye; ophthalmic solution; tetrahydroisoquinoline derivative

Year:  2012        PMID： 24900456      PMCID： PMC4025648          DOI： 10.1021/ml2002482

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


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