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

  • J Med Chem. 2026 Jan 8;69(1):205-227. doi: 10.1021/acs.jmedchem.5c02250.
Manman Sun  1 ,  Jie Zhang  2 ,  Aohui Hu  1 ,  Jiacheng Wang  1 ,  Kaile Yao  1 ,  Xuebo Yang  1 ,  Wanxing Ni  1 ,  Lingchen Tan  1  3 ,  Yu Zhang  2 ,  Linxiang Zhao  1 ,  Min Huang  1  4  5
Affiliations
  • 1. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2. Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3. College of Life and Health Sciences, Northeastern University, Shenyang 110169, China.
  • 4. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
  • 5. Joint International Research Laboratory of Intelligent Drug Delivery Systems, Ministry of Education, Shenyang 110016, China.
PMID: 41432294 DOI: 10.1021/acs.jmedchem.5c02250
Abstract

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 25 as the most potent candidate. Compound 25 demonstrated stronger LFA-1 binding affinity than Lifitegrast, and potently inhibited ICAM-1-mediated cell adhesion. Compound 25 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 25 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 25 as a promising next-generation LFA-1 inhibitor for DED treatment.

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