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038E5L962W

038E5L962W

Synopsis, Chemistry

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Also known as: 1025967-78-5, Xiidra, Sar 1118, Sar-1118, Shp606, Shp-606

Molecular Formula

C₂₉H₂₄Cl₂N₂O₇S

Molecular Weight

615.5 g/mol

InChI Key

JFOZKMSJYSPYLN-QHCPKHFHSA-N

FDA UNII

038E5L962W

Lifitegrast is a FDA approved drug for the treatment of keratoconjunctivitis sicca (dry eye syndrome). It is a tetrahydroisoquinoline derivative and lymphocyte function-associated antigen-1 ( LFA-1) antagonist that was discovered through the rational design process. The ophthalmic solution was approved in July, 2016 under the trade name Xiidra. It has shown to protect the corneal surface and alleviate the symptoms of dry eye syndrome with fast onset of action and well tolerated profile in both local and systemic setting.

Lifitegrast is a Lymphocyte Function-Associated Antigen-1 Antagonist. The mechanism of action of lifitegrast is as a Lymphocyte Function-Associated Antigen-1 Antagonist.

1 2D Structure

038E5L962W

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

(2S)-2-[[2-(1-benzofuran-6-carbonyl)-5,7-dichloro-3,4-dihydro-1H-isoquinoline-6-carbonyl]amino]-3-(3-methylsulfonylphenyl)propanoic acid

2.1.2 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

2.1.3 InChI Key

JFOZKMSJYSPYLN-QHCPKHFHSA-N

2.1.4 Canonical SMILES

CS(=O)(=O)C1=CC=CC(=C1)CC(C(=O)O)NC(=O)C2=C(C=C3CN(CCC3=C2Cl)C(=O)C4=CC5=C(C=C4)C=CO5)Cl

2.1.5 Isomeric 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

2.2 Other Identifiers

2.2.1 UNII

038E5L962W

2.3 Synonyms

2.3.1 MeSH Synonyms

1. (2s)-2-(((2-(benzofuran-6-ylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6- Yl)carbonyl)amino)-3-(3-(methylsulfonyl)phenyl)propanoic Acid

2. L-phenylalanine, N-((2-(6-benzofuranylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl)carbonyl)-3-(methylsulfonyl)-

3. Lifitegrast Ophthalmic Solution

4. Sar 1118

5. Sar-1118

6. Shp-606

7. Shp606

8. Xiidra

2.3.2 Depositor-Supplied Synonyms

1. 1025967-78-5

2. Xiidra

3. Sar 1118

4. Sar-1118

5. Shp606

6. Shp-606

7. (s)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic Acid

8. Chembl2048028

9. 038e5l962w

10. (2s)-2-(((2-(benzofuran-6-ylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6- Yl)carbonyl)amino)-3-(3-(methylsulfonyl)phenyl)propanoic Acid

11. L-phenylalanine, N-((2-(6-benzofuranylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl)carbonyl)-3-(methylsulfonyl)-

12. L-phenylalanine, N-[[2-(6-benzofuranylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl]carbonyl]-3-(methylsulfonyl)-

13. Lifitegrast [usan:inn]

14. Unii-038e5l962w

15. Sar1118

16. Xiidra (tn)

17. Lifitegrast [mi]

18. Lifitegrast [inn]

19. Lifitegrast (usan/inn)

20. Lifitegrast [usan]

21. Lifitegrast; Sar 1118

22. Lifitegrast [who-dd]

23. Lifitegrast Ophthalmic Solution

24. Gtpl7533

25. Schembl2632068

26. Amy4450

27. Dtxsid60145345

28. Lifitegrast [orange Book]

29. Chebi:133023

30. Ex-a2582

31. Bdbm50386331

32. Mfcd28502439

33. S3714

34. Zinc84668739

35. Ccg-270245

36. Cs-6264

37. Db11611

38. Compound 1g [pmid: 24900456]

39. Ac-32534

40. Ds-20052

41. Hy-19344

42. D10374

43. A900838

44. Q23044263

45. (2s)-2-[[2-(1-benzofuran-6-carbonyl)-5,7-dichloro3,4-dihydro-1h-isoquinoline-6-carbonyl]amino]-3-(3-methylsulfonylphenyl)propanoic Acid

46. N-[[2-(6-benzofuranylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl]carbonyl]-3-(methylsulfonyl)-l-phenylalanine

47. N-[2-(1-benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carbonyl]-3-(methanesulfonyl)-l-phenylalanine

2.4 Create Date

2006-12-18

3 Chemical and Physical Properties

Molecular Formula	C₂₉H₂₄Cl₂N₂O₇S
Molecular Weight	615.5 g/mol
XLogP3	4.7
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	7
Exact Mass	614.0681277 g/mol
Monoisotopic Mass	614.0681277 g/mol
Topological Polar Surface Area	142 Å²
Heavy Atom Count	41
Formal Charge	0
Complexity	1100
Isotope Atom Count	0
Defined Atom Stereocenter Count	1
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

For the treatment of signs and symptoms of keratoconjunctivitis sicca (dry eye syndrome).

FDA Label

Treatment of dry eye disease

5 Pharmacology and Biochemistry

5.1 Pharmacology

Lifitegrast addresses both the symptoms and the resulting ocular surface damage by interfering with ocular inflammatory cycle. Lifitegrast is a lymphocyte functionassociated antigen-1 antagonist through direct competitive antagonism and sequentially inhibits the T-cell recruitment, activation, and proinflammatory cytokine release associated with dry eye syndrome.

5.2 MeSH Pharmacological Classification

Ophthalmic Solutions

Sterile solutions that are intended for instillation into the eye. It does not include solutions for cleaning eyeglasses or CONTACT LENS SOLUTIONS. (See all compounds classified as Ophthalmic Solutions.)

5.3 FDA Pharmacological Classification

5.3.1 Active Moiety

LIFITEGRAST

5.3.2 FDA UNII

038E5L962W

5.3.3 Pharmacological Classes

Lymphocyte Function-Associated Antigen-1 Antagonists [MoA]; Lymphocyte Function-Associated Antigen-1 Antagonist [EPC]

5.4 ATC Code

S - Sensory organs

S01 - Ophthalmologicals

S01X - Other ophthalmologicals

S01XA - Other ophthalmologicals

S01XA25 - Lifitegrast

5.5 Absorption, Distribution and Excretion

Absorption

The mean peak plasma concentration (Cmax) of 1.70ng/mL was reached within 15 minutes of application. Quantifiable trough plasma concentrations ranged from 0.55 ng/mL to 3.74 ng/mL. Observations show limited systemic exposure that produces significant clinical outcomes.

Route of Elimination

Not possible to perform mass balance study to determine the main route of elimination.

Clearance

Not possible to calculate clearance rate based on plasma concentrations of lifitegrast, but reported to be relatively fast in rat I.V. pharmacokinetics study. It is predicted that lifitegrast is cleared via nasal and subsequently gastrointestinal tract.

5.6 Metabolism/Metabolites

Based on the findings of an in vitro metabolism study using fresh human hepatocytes, lifitegrast does not appear to undergo significant metabolism.

5.7 Biological Half-Life

Not possible to calculate plasma elimination half-life based on plasma concentrations of lifitegrast, but reported to be relatively short in rat I.V. pharmacokinetics study.

5.8 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 proliferation/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, inflammatory mediators, chemokines, TNF-, and IL-1 in human peripheral blood mononuclear cells.