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

作者：Zhong Min^*; Gadek Thomas R; Bui Minna; Shen Wang; Burnier John; Barr Kenneth J; Hanan Emily J; Oslob Johan D; Yu Chul H; Zhu Jiang; Arkin Michelle R; Evanchik Marc J; Flanagan W Mike; Hoch Ute; Hyde Jennifer; Prabhu Saileta; Silverman Jeffrey A; Wright Jasmin

来源：ACS Medicinal Chemistry Letters, 2012, 3(3): 203-206.

DOI：10.1021/ml2002482

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

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.

• 出版日期2012-3