Application Pharmacodynamics
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lifitegrast

Application Pharmacodynamics
Product Name
lifitegrast
CAS No.
1025967-78-5
Chemical Name
lifitegrast
Synonyms
Lifitegrast-d4;liftegrast;Lifitegrast Impurity;CS-2633;(S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid;Amipak;SHP-606;SAR 1118;Rituxite;Litastat
CBNumber
CB92738258
Molecular Formula
C29H24Cl2N2O7S
Formula Weight
615.48
MOL File
1025967-78-5.mol
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lifitegrast Property

Melting point:
>163°C (dec.)
Boiling point:
811.9±65.0 °C(Predicted)
Density 
1.479±0.06 g/cm3(Predicted)
storage temp. 
Hygroscopic, -20°C Freezer, Under inert atmosphere
solubility 
DMSO (Slightly, Heated, Sonicated), Methanol (Slightly, Sonicated)
form 
Solid
pka
3.14±0.10(Predicted)
color 
White to Off-White
Stability:
Hygroscopic
InChIKey
JFOZKMSJYSPYLN-QHCPKHFHSA-N
SMILES
C(O)(=O)[C@H](CC1=CC=CC(S(C)(=O)=O)=C1)NC(C1C(Cl)=CC2=C(C=1Cl)CCN(C(C1C=C3OC=CC3=CC=1)=O)C2)=O
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Hazard and Precautionary Statements (GHS)

Symbol(GHS)
Signal word
Warning
Hazard statements

H302Harmful if swallowed

H315Causes skin irritation

H319Causes serious eye irritation

H335May cause respiratory irritation

Precautionary statements

P261Avoid breathing dust/fume/gas/mist/vapours/spray.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

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N-Bromosuccinimide Price

Cayman Chemical
Product number
22588
Product name
Lifitegrast
Purity
≥98%
Packaging
5mg
Price
$32
Updated
2024/03/01
Cayman Chemical
Product number
22588
Product name
Lifitegrast
Purity
≥98%
Packaging
10mg
Price
$61
Updated
2024/03/01
Cayman Chemical
Product number
22588
Product name
Lifitegrast
Purity
≥98%
Packaging
25mg
Price
$139
Updated
2024/03/01
Cayman Chemical
Product number
22588
Product name
Lifitegrast
Purity
≥98%
Packaging
50mg
Price
$243
Updated
2024/03/01
TRC
Product number
L465955
Product name
Lifitegrast
Packaging
100mg
Price
$275
Updated
2021/12/16
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lifitegrast Chemical Properties,Usage,Production

Application

Lifitegrast is used for the treatment of signs and symptons of dry eye diseases. It also Inhibites corneal inflammation that is capable of causing pains, blurred vision and ocular discomfort in sufferer.

Pharmacodynamics

Lifitegrast is soluble in a phosphate-buffered saline at concentrations up to and exceeding 200 mg/ml, which allows up to a 10% (100 mg/ml) preparation that has an osmolality relatively equal to that of human tears (300 mOsm/L). This is preferred to reduce the likelihood of local irritation. In a study that evaluated the conjunctiva in mice, lifitegrast compared to vehicle demonstrated a statistically significant reduction in the expression of inflammatory mediators, including interferon gamma and chemokine ligand 9. In this same study, lifitegrast increased the number of conjunctival goblet cells and goblet cell area by 39% and 22%, respectively (p < 0.05 for both), resulting in a therapeutic improvement within 5 days. In an in vivo study of dogs with keratoconjuctivitis, a 1% solution of lifitegrast administered 3 times a day significantly increased tear production at the end of 12 weeks (Schirmer tear test, 3.4 to 5.8 mm; p < 0.025). In a separate in vitro study, lifitegrast exhibited a preferred negative result in the Ames test and low affinity for cytochrome P450 CYP3A4 and CYP2C9 enzymes (IC50 > 20 µM and IC50 = 3.0 µM, respectively) and the human Ether-à-go-go-Related Gene (hERG, IC50 > 20 µM)[1].

Description

Lifitegrast (Xiidra; lifitegrast sodium; SAR1118; SHP606; SPD606) is a lymphocyte functionassociated antigen-1 (LFA-1) antagonist. It inhibits T-cell inflammation by blocking the binding of two key surface proteins (LFA-1 and ICAM-1) that mediate the chronic inflammatory cascade associated with dry eye disease. In a phase III clinical trial, lifitegrast 5% ophthalmic solution (50 mg/mL) is administered as a single 0.2mL eye drop twice a day into each eye for an 84 day treatment period.

Lifitegrast does not currently have Marketing Authorisation in the EU for any indication. Lifitegrast is licensed for use in the USA for treatment of the signs and symptoms of dry eye disease. The most common adverse reactions (incidence 5-25%) reported following the use of lifitegrast are instillation site irritation, dysgeusia, and decreased visual acuity.

Chemical Properties

Lifitegrast is a white to off-white powder which is soluble in water.

Uses

Lifitegrast is used for the treatment of signs and symptons of dry eye diseases. It also Inhibites corneal inflammation that is capable of causing pains, blurred vision and ocular discomfort in sufferer.

Definition

ChEBI: An N-acyl-L-alpha-amino acid obtained by formal condensation of the carboxy group of N-[2-(1-benzofuran-6-carbonyl)]-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid with he amino group of 3-(methanesulfonyl)-L-phenylalanine. Used for treatment of keratoconjunctivitis sicca (dry eye syndrome).

Indications

Topical lifitegrast was approved by the FDA for the treatment of dry eye. Lifitegrast decreases inflammation by blocking the interaction between intercellular adhesion molcule 1 and lymphocyte function- -associated antigen 1. In four, large, multicellular, randomized clinical trials, lifitegrast was shown to be effective in improving the signs and symptoms of dry eye. The side effects of lifitegrast include transient ocular irritation and dysgeusia. Further studies are needed to explore the effectiveness of combination therapy such as the concomitant use of topical cyclosporine and topical liftegrast.

Mechanism of action

Lifitegrast binds to the integrin lymphocyte function-associated antigen-1 (LFA-1), a cell surface protein found on leukocytes and blocks the interaction of LFA-1 with its cognate ligand intercellular adhesion molecule-1 (ICAM-1). ICAM-1 may be overexpressed in corneal and conjunctival tissues in dry eye disease. LFA-1/ICAM-1 interaction can contribute to the formation of an immunological synapse resulting in T-cell activation and migration to target tissues. In vitro studies demonstrated that lifitegrast may inhibit T-cell adhesion to ICAM-1 in a human T-cell line and may inhibit secretion of inflammatory cytokines in human peripheral blood mononuclear cells. The exact mechanism of action of lifitegrast in dry eye disease is not known.

Pharmacokinetics

In a subset of dry eye disease patients (n=47) enrolled in a Phase 3 trial, the pre-dose (trough) plasma concentrations of lifitegrast were measured after 180 and 360 days of topical ocular dosing (1 drop twice daily) with Xiidra (lifitegrast ophthalmic solution) 5%. A total of nine (9) of the 47 patients (19%) had plasma lifitegrast trough concentrations above 0.5 ng/mL (the lower limit of assay quantitation). Trough plasma concentrations that could be quantitated ranged from 0.55 ng/mL to 3.74 ng/mL.

Side effects

A multicenter, randomized, double-masked, placebo-controlled phase 3 study (n = 331) evaluating the safety of lifitegrast ophthalmic solution for the treatment of dry eye disease reported the most common non-ocular effect was dysgeusia (change in taste) occurring in 16.4% of patients in the lifitegrast group and 1.8% of the placebo group.

Synthesis

After Boc protection, reaction with sodium methanesulfinate in the presence of copper iodide, K2CO3, and L-proline gave rise to sulfonate 176. Esterification of 176 with benzyl alcohol followed by removal of the Boc group within 177 yielded the corresponding HCl salt of the aminoester 178. Amide bond coupling with acid 179 furnished amide 180, which was then subjected to 4 N HCl in dioxane resulting in trityl removal and arrival at HCl salt 181 in 88% yield over two steps. Tetrahydroisoquinoline 181 was then coupled with commercial benzofuranyl acid 182 to give rise to lifitegrast benzyl ester in 90% yield. Finally, saponification delivered lifitegrast (XIX) in 88% yield.
Tetrahydroisoquinoline-6-carboxylic acid 179 was prepared starting from commercial 3,5-dichlorobenzaldehyde 183. Reductive amination with 1-chloro-2-aminoethane 184 gave chloroethyl amine 185, which underwent an efficient intramolecular Friedel-Crafts reaction using AlCl3 to generate the corresponding tetrahydroisoquinoline 186 in 91% yield. N-Tritylation of 186 proceeded in 89% yield, and this was followed by a directed o-metalation reaction and carbon dioxide quench to furnish the requisite acid 179 in 75% yield.

References

[1] Stacy L. Haber. “Lifitegrast: a novel drug for patients with dry eye disease.” ACS Applied Bio Materials (2019).

lifitegrast Preparation Products And Raw materials

Raw materials

Preparation Products

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lifitegrast Suppliers

TOKYO CHEMICAL INDUSTRY CO., LTD.
Tel
03-36680489
Fax
03-3668-0520
Email
Sales-JP@TCIchemicals.com
Country
Japan
ProdList
28387
Advantage
80
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View Lastest Price from lifitegrast manufacturers

BEIJING SJAR TECHNOLOGY DEVELOPMENT CO., LTD.
Product
Lifitegrast 1025967-78-5
Price
US $0.00/g
Min. Order
1g
Purity
More Than 99%
Supply Ability
100kg/Month
Release date
2024-09-13
WUHAN FORTUNA CHEMICAL CO., LTD
Product
Lifitegrast 1025967-78-5
Price
US $0.00/KG
Min. Order
1KG
Purity
99%min
Supply Ability
100kg
Release date
2021-09-13
shandong perfect biotechnology co.ltd
Product
Lifitegrast 1025967-78-5
Price
US $0.00/g
Min. Order
1g
Purity
98% HPLC
Supply Ability
100KG
Release date
2023-08-14

1025967-78-5, lifitegrastRelated Search:


  • ifitegrast
  • CS-2633
  • Lifitegrast(API)
  • SAR-1118;SAR1118
  • Lifitegrast-d4
  • Lifitegrast Impurity
  • lifitegrast
  • Lifitegrast, SAR 1118
  • L-Phenylalanine,N-[[2-(6-benzofuranylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl]carbonyl]-3-(methylsulfonyl)-
  • N-[[2-(6-Benzofuranylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl]carbonyl]-3-(methylsulfonyl)-L-phenylalanine
  • SAR 1118
  • (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid
  • (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic
  • liftegrast
  • Lifitegrast (This product is only available in Japan.)
  • Lifitegrast (Xiidra)
  • SHP-606
  • Lifitegras
  • Lifitegrast Lifitegrast API
  • Lifitegrast-d6
  • Amipak
  • Litahistite
  • Rituxite
  • SHP-606|||SAR 1118
  • Litastat
  • Litakast
  • 1025967-78-5
  • 1025967-90-4
  • C29H24Cl2N2O7S
  • API