Design, Synthesis, and Biological Evaluation of a Series of Novel LFA-1 Antagonists with Enhanced Potency and Ocular Safety for Dry Eye Disease

Dry eye disease (DED) is a chronic inflammatory disorder in which the LFA-1/ICAM-1 interaction plays a central immunopathological role. Lifitegrast, the first approved LFA-1 antagonist for DED treatment, is limited by suboptimal efficacy and notable ocular irritation, highlighting the need for further optimization. Here, we designed and synthesized a series of novel LFA-1 inhibitors and identified compound <b>25</b> as the most potent candidate. Compound <b>25</b> demonstrated stronger LFA-1 binding affinity than Lifitegrast, and potently inhibited ICAM-1-mediated cell adhesion. Compound <b>25</b> protected human corneal epithelial cells from inflammatory hyperosmotic stress. Pharmacokinetic studies showed that it possessed a favorable ocular tissue distribution with negligible systemic exposure. In a benzalkonium chloride-induced DED rat model, compound <b>25</b> significantly improved corneal repair, tear secretion, and reduced pro-inflammatory cytokines. Furthermore, it exhibited excellent ocular safety under both single and repeated dosing. These findings suggest compound <b>25</b> as a promising next-generation LFA-1 inhibitor for DED treatment.