Lifitegrast
[CAS# 1025967-78-5]

Identification

• Classification: API >> Other chemicals
• Name: Lifitegrast
• Synonyms: N-[[2-(6-Benzofuranylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl]carbonyl]-3-(methylsulfonyl)-L-phenylalanine; SAR 1118
• Molecular Formula: C₂₉H₂₄Cl₂N₂O₇S
• Molecular Weight: 615.48
• CAS Registry Number: 1025967-78-5
• EC Number: 813-044-8
• SMILES: CS(=O)(=O)C1=CC=CC(=C1)C[C@@H](C(=O)O)NC(=O)C2=C(C=C3CN(CCC3=C2Cl)C(=O)C4=CC5=C(C=C4)C=CO5)Cl

Properties

• Solubility: Insoluble (3.4E^-4 g/L) (25 °C), Calc.^*
• Density: 1.479±0.06 g/cm³ (20 °C 760 Torr), Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (©1994-2015 ACD/Labs)

Safety Data

• Hazard Symbols: GHS08 Warning
• Risk Statements: H361
• Safety Statements: P203-P280-P318-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Reproductive toxicity	Repr.	2	H361

Discovery and Applications

Lifitegrast is a small-molecule integrin antagonist that was developed as a novel therapeutic agent for the treatment of dry eye disease, a common condition characterized by inflammation and discomfort in the eyes due to insufficient lubrication. The discovery of Lifitegrast marked a significant advancement in the management of this chronic condition, offering a targeted approach that addresses the underlying inflammatory pathways involved in dry eye disease.

The development of Lifitegrast was driven by the understanding that inflammation plays a crucial role in the pathogenesis of dry eye disease. Specifically, it was recognized that the interaction between the lymphocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) is a key mediator of the inflammatory response in the ocular surface. This interaction leads to the activation and migration of T-cells, contributing to the inflammation and damage observed in dry eye disease. Lifitegrast was designed to inhibit this interaction, thereby reducing T-cell activation and the associated inflammatory cascade.

Chemically, Lifitegrast is an N-benzyl substituted 1,3,4-thiadiazole derivative that binds to the LFA-1 integrin on T-cells, preventing it from interacting with ICAM-1 on the surface of endothelial cells and epithelial cells. This mechanism of action is highly specific, allowing Lifitegrast to effectively reduce inflammation without affecting other cellular processes, making it a promising candidate for the treatment of dry eye disease.

The clinical application of Lifitegrast was first realized when it demonstrated significant efficacy in reducing the signs and symptoms of dry eye disease in clinical trials. Patients treated with Lifitegrast showed improvements in both the objective measures of eye dryness and the subjective symptoms of discomfort and irritation. This led to the approval of Lifitegrast by the U.S. Food and Drug Administration (FDA) in 2016, making it one of the first drugs specifically approved for the treatment of dry eye disease.

Lifitegrast is administered as an eye drop solution, typically used twice daily. The convenience of this dosing regimen, combined with its efficacy in reducing ocular surface inflammation, has made it a valuable option for patients suffering from dry eye disease. Moreover, Lifitegrast has been well-tolerated in patients, with the most common side effects being mild and transient, such as irritation at the application site and dysgeusia, a change in taste perception.

The impact of Lifitegrast extends beyond its role in treating dry eye disease. The discovery and development of this drug have highlighted the importance of targeting specific molecular interactions in the treatment of inflammatory diseases. This has opened up new avenues of research into integrin antagonists for other inflammatory conditions, suggesting that Lifitegrast may serve as a model for the development of similar therapies in the future.

Overall, Lifitegrast represents a significant step forward in the treatment of dry eye disease, providing relief for millions of patients worldwide. Its discovery underscores the potential of targeted therapies in addressing complex inflammatory conditions and offers a template for the development of future integrin-based treatments.

References

2017. Lifitegrast for the Treatment of Dry Eye Disease: Results of a Phase III, Randomized, Double-Masked, Placebo-Controlled Trial (OPUS-3). Ophthalmology, 124(1).
DOI: 10.1016/j.ophtha.2016.09.025

2019. Lifitegrast Ophthalmic Solution 5.0% for Treatment of Dry Eye Disease: Overview of Clinical Trial Program. Journal of Pharmacy & Pharmaceutical Sciences, 22(1).
DOI: 10.18433/jpps29895

2023. Real-world treatment patterns of OTX-101 ophthalmic solution, cyclosporine ophthalmic emulsion, and lifitegrast ophthalmic solution in patients with dry eye disease: a retrospective analysis. BMC Ophthalmology, 23(1).
DOI: 10.1186/s12886-023-03174-y