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

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• 作者：Min Zhong ; Thomas R. Gadek ; Minna Bui ; Wang Shen ; John Burnier ; Kenneth J. Barr ; Emily J. Hanan ; Johan D. Oslob ; Chul H. Yu ; Jiang Zhu ; Michelle R. Arkin ; Marc J. Evanchik ; W. Mike Flanagan ; Ute Hoch ; Jennifer Hyde ; Saileta Prabhu ; Jeffrey A. Silverman ; Jasmin Wright
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：3
• 期：3
• 页码：203-206
• 全文大小：200K
• 年卷期：v.3,no.3(March 8, 2012)
• ISSN：1948-5875

文摘

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.

Keywords:

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