Lifitegrast [N-{[2-(1-Benzofuran-6-ylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl]carbonyl}-3-(methylsulfonyl)-L-phenylalanine]
is a potent novel small molecule lymphocyte function-associated antigen-1
(LFA-1/ICAM-1) antagonist for a broad range of ocular inflammatory conditions
including dry eye and diabetic macular edema. It represents a first-in-class
integrin anti-inflammatory specifically engineered for ophthalmic use [1].
Lifitegrast is designed with the
hypothesis that inhibition of the LFA-1/ICAM-1 interaction may be an
appropriate pharmacologic target for breaking the constant cycle of
T-cell-mediated inflammation associated with dry eye. The anti-inflammatory
effects of LFA-1 inhibition have been biologically validated in experimental
models of chronic inflammation, including uveitis, diabetic retinopathy, and
keratoconjunctivitis.
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| Lifitegrast: 2D and 3D Structure |
Lifitegrast is an ICAM-1 decoy
and prevents binding of LFA-1 to native ICAM-1 expressed on the surface of
inflamed epithelial, endothelial, and antigen presenting cells. It is a member
of a series of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1
antagonists, which were shown to bind the I-domain of the CD11α subunit of LFA-1 and serve as direct competitive
antagonists of LFA-1 binding to ICAM-1 [2, 3].
On July 11, 2016 Lifitegrast was
approved as a twice-daily eye drop solution indicated for the treatment of the
signs and symptoms of dry eye disease in adult patients.
Dry Eye
[keratoconjunctivitis sicca (KCS), keratitis sicca, or xerophthalmia]
Dry eye is a complex disorder of
the ocular surface characterized by symptoms of discomfort, decreased tear
quality, and chronic inflammation. Although the cause of dry eye is
multifactorial, a common pathway is the establishment of a proinflammatory state
leading to activation of T-cell-mediated immune responses, cytokine release,
and hyperosmolar tears. The resulting inflammatory milieu stimulates corneal
neural fibers resulting in sensations of ocular discomfort and dryness.
Activation and homing of lymphocytes
to the ocular surface are central to the chronic inflammatory process and
influenced by the binding of the T-cell integrin, lymphocyte function antigen-1
(LFA-1; CD11α /CD18; αLβ2), to its cognate ligand, intercellular adhesion
molecule-1 (ICAM-1; CD54) expressed on the cell surface of inflamed
epithelium.7 Increased expression of ICAM-1 is demonstrated at both the mRNA
and protein levels in conjunctival epithelial/lacrimal acinar cells in patients
with dry eye,10 along with elevated levels of inflammatory T-cell-mediated
cytokines in the tear film.11
Lifitegrast
(0.5%) as a topically administered LFA-1 inhibitor
Phase III study demonstrated
superiority of Lifitegrast 5.0% in reducing ocular surface epithelial lesions
compared with placebo. These findings were supported by statistically
significant improvements observed in the superior and total corneal regions
after 84 days of treatment. Furthermore, benefits in corneal fluorescein
staining were supported by improvements in conjunctival lissamine staining in
the nasal and total conjunctival regions with statistical significance observed
as early as day 14 and benefit maintained through day 84.
The study provides evidence that
use of Lifitegrast, a topically administered LFA-1 inhibitor, can reduce
inflammatory changes of the ocular surface associated with dry eye disease as
early as week 2 when administered twice daily over a 12-week treatment period.
Lifitegrast demonstrated evidence
of reduced ocular surface inflammation as early as day 14 as measured by
lissamine. The relatively rapid onset of action may be attributable to broad
inhibition of inflammatory cytokines associated with dry eye and maintenance of
sustained inhibitory concentrations of drug in the tear film up to 24 hours
after a single dose. Human clinical data of Lifitegrast have demonstrated that
a compound possessing great potency against the biological target, good
intrinsic solubility, poor oral bioavailability, and fast clearance can also be
developed into a safe and efficacious ophthalmic treatment.
Dosages
and Approvals:
Lifitegrast 5%ophthalmic solution
(Tradename: Xiidra) was approved by the U.S. Food and
Drug Administration (FDA) on July 11, 2016 as a twice-daily eye drop solution
indicated for the treatment of the signs and symptoms of dry eye disease in
adult patients. Xiidra is the only prescription eye drop indicated for the
treatment of both signs and symptoms of this condition. It is dosed twice per
day, approximately 12 hours apart, in each eye. Shire plc is credited with
discovery and development of Lifitegrast. Shire expects to launch Xiidra in the
United States in the third quarter of 2016.
Reported
Activities for Lifitegrast
IC50 (Inhibition of Binding
of Hut-78 cells to Immobilized ICAM-1) = 0.009 uM
IC50 (Inhibition of
Jurkat T-cell Attachment to ICAM-1) = 2.98 nM
Summary
Common name: SAR 1118; SAR-1118; SAR1118;
Lifitegrast
Trademarks: Xiidra
Molecular Formula: C29H24Cl2N2O7S
CAS Registry Number: 1025967-78-5
CAS Name: N-{[2-(1-Benzofuran-6-ylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl]carbonyl}-3-(methylsulfonyl)-L-phenylalanine
Molecular Weight: 615.48
SMILES:CS(=O)(=O)c1cccc(c1)C[C@@H](C(=O)O)NC(=O)c2c(cc3c(c2Cl)CCN(C3)C(=O)c4ccc5ccoc5c4)Cl
InChI Key: JFOZKMSJYSPYLN-QHCPKHFHSA-N
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
Mechanism of Action: LFA-1/ICAM-1
antagonists; Lymphocyte function-associated antigen-1 Inhibitor
Activity: Treatment of Dry Eyes; Treatment of Keratoconjunctivitis
Sicca (KCS), Keratitis Sicca, or Xerophthalmia; Ophthalmic Agents
Status: Launched 2016 (US)
Chemical Class: Tetrahydroisoquinoline;
Amides; Amino Acids; Chlorobenzenes; Small-molecules; Chlorine containing; Methylsulfonyl
containing; L-phenylalanine
Originator: Shire Pharmaceuticals
