lifitegrast   Click here for help

GtoPdb Ligand ID: 7533

Synonyms: compound 1g [PMID: 24900456] | SAR 1118 | SAR-1118 | SAR-1118-023 | Xiidra®
Approved drug Immunopharmacology Ligand
lifitegrast is an approved drug (FDA (2016))
Compound class: Synthetic organic
Comment: It is postulated that lifitegrast (SAR 1118) interacts with the lymphocyte function-associated antigen-1 (LFA-1) to inhbit the LFA-1/ICAM-1 adhesion interaction and was approved for the treatment of Dry Ey in 2016 [7,9]. LFA-1 is a heterodimeric member of the β2 integrin family which is essential for adhesion, migration, and proliferation of T cells at sites of inflammation, and is involved in T cell specific immune responses through the formation of adhesive interactions and immunological synapses. Intercellular adhesion molecule‑1 (ICAM‑1) is the cognate ligand of LFA-1.The compound formulation is claimed in patent WO2014100135 [7].
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 8
Hydrogen bond donors 2
Rotatable bonds 9
Topological polar surface area 142.37
Molecular weight 614.07
XLogP 4.69
No. Lipinski's rules broken 0
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Canonical SMILES OC(=O)C(NC(=O)c1c(Cl)cc2c(c1Cl)CCN(C2)C(=O)c1ccc2c(c1)occ2)Cc1cccc(c1)S(=O)(=O)C
Isomeric SMILES OC(=O)[C@@H](NC(=O)c1c(Cl)cc2c(c1Cl)CCN(C2)C(=O)c1ccc2c(c1)occ2)Cc1cccc(c1)S(=O)(=O)C
InChI InChI=1S/C29H24Cl2N2O7S/c1-41(38,39)20-4-2-3-16(11-20)12-23(29(36)37)32-27(34)25-22(30)13-19-15-33(9-7-21(19)26(25)31)28(35)18-6-5-17-8-10-40-24(17)14-18/h2-6,8,10-11,13-14,23H,7,9,12,15H2,1H3,(H,32,34)(H,36,37)/t23-/m0/s1
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Summary of Clinical Use Click here for help
Lifitegrast is a topical integrin antagonist approved by the US FDA (July 2016) for the treatment of keratoconjunctivitis sicca (dry eye disease) [8-9].
Phase 3 trial results are published in [8].
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Dry eye disease is believed to be a chronic inflammatory condition [5]. The disease is accompanied by an increase of ICAM-1 expression, which is postulated to underpin the LFA-1/ICAM-1 interaction which supports the pathological inflammatory and specific T-cell regulated immune responses in this condition. Although the mechanism of action of lifitegrast in dry eye disease is not fully resolved, the drug has been shown to antagonise the interaction between ICAM-1 and LFA-1 to bring about a reduction in the signs and symptoms of the condition [6].

Giblin and Lemieux (2006) [3] review LFA-1 as a key regulator of immune function and discuss the mechanisms employed by the different types of LFA-1-based therapeutics in development [1]. Descriptive content in patent WO2015189265 [2] alludes to lifitegrast being an α/β I allosteric LFA-1 inhibitor; this class of inhibitors are ligand mimetics based on amino acid sequence of the LFA-1 binding region of ICAM, which are found to compete for binding of an internal ligand of LFA-1 beta chain. A more extensive review of integrin modulators in the patent literature is provided by Kapp et al. (2013) [4].