Discovery of tetrahydroisoquinoline (THIQ) derivatives as potent and orally bioavailable LFA-1/ICAM-1 antagonists

Zhong, Min; Wang, Shen; Barr, Kenneth J.; Arbitrario, Jennifer P.; Arkin, Michelle R.; Bui, Minna; Chen, Teresa C.; Cunningham, Brian C.; Evanchik, Marc J.; Hanan, Emily J.; Hoch, Ute; Huen, Karen; Hyde, Jennifer; Kumer, Jeffery L.; Lac, Teresa; Lawrence, Chris E.; Martell, J.; Oslob, Johan D.; Paulvannan, Kumar; Prabhu, Saileta; Silverman, Jeffrey A.; Wright, Jasmin; Yu, Chul H.; Zhu, Jiang; Flanagan, W. Mike

doi:10.1016/j.bmcl.2010.06.145

Cited by 14 publications

(12 citation statements)

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“…It has been established that the structure of central tetrahydroisoquinoline (THIQ) scaffold (Fig. 2) is a pharmacophore that is essential for LFA-1/ICAM-1 antagonist activity [14]. Previous SAR studies have shown that an aromatic group in the "left-wing" residue is necessary for LFA-1/ICAM-1 antagonist activity [15].…”

Section: Design Of Lifitegrast Analoguesmentioning

confidence: 99%

“…Analogues 1a-1e were generated through the synthetic route outlined in Scheme 2. Amide intermediate (5) was treated with benzofuran-6-sulfonyl chloride (10), benzofuran-6-ylmethanamine (14), 2-(benzofuran-5-yl) acetic acid (16) [18], [1,2,4]triazolo [1,5-a]pyridine-6-carboxylic acid (18) [19] and 3-ethynylbenzoic acid 20 [20] in DCM in the presence of condensating agent HATU or CDI to yield benzyl group analogues 11, 15, 17, 19 and 21, which provided analogues 1a-1e in the presence of debenzylation agent H 2 or TMSOK in MeOH or THF through removing the benzyl group [21]. The condensation activity of carboxyl with amino is stronger than that of amine with amino group, so the yield of compound 11, 17, 19, 21 was higher than that of compound 15.…”

Section: Chemistrymentioning

confidence: 99%

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Design, synthesis, and LFA-1/ICAM-1 antagonist activity evaluation of Lifitegrast analogues

et al. 2022

Med Chem Res

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The interaction between Lymphocyte function-associated antigen 1 (LFA-1) and intercellular-adhesion molecule-1 (ICAM-1) plays important roles in the cell-mediated immune response and inflammation associated with dry eye disease. LFA-1/ICAM-1 antagonists can be used for the treatment of dry eye disease, such as Lifitegrast which has been approved by the FDA in 2016 as a new drug for the treatment of dry eye disease. In this study, we designed and synthesized some new structure compounds that are analogues to Lifitegrast, and their biological activities were evaluated by in vitro cell-based assay and also by in vivo mouse dry eye model. Our results demonstrated that one of these analogues of Lifitegrast (compound 1b) showed good LFA-1/ICAM-1 antagonist activity in in vitro assay; meanwhile, it also significantly reduced ocular surface epithelial cells damage, increased goblet cell density in dry eye mouse and highly improved the symptoms of dry eye mouse.

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Section: Design Of Lifitegrast Analoguesmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Design, synthesis, and LFA-1/ICAM-1 antagonist activity evaluation of Lifitegrast analogues

et al. 2022

Med Chem Res

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“…12 Lifitegrast is well-tolerated in patients, and provides rapid and sustained relief of DES compared to traditional treatments. [13][14][15][16] Recently, the FDA approved a 5% lifitegrast ophthalmic solution (Xiidra TM -Shire) as an eye-drop-based therapy for DES. 17,18 Of note, the concentration of lifitegrast (in Xiidra) is 81.2 mM (50 mg/mL), which is 81,200 higher than the concentration required to treat severe cases of DES (1 µM).…”

Section: Introductionmentioning

confidence: 99%

An Engineered Contact Lens for Passive and Sustained Release of Lifitegrast, an Anti-Dry Eye Syndrome Drug

Lee

et al. 2021

Preprint

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Lifitegrast is an FDA-approved drug that inhibits T-cell mediated inflammation associated with dry eye syndrome (DES). Lifitegrast is a potent inhibitor of the interaction between LFA-1 on T-cells and ICAM-1 on endothelial cells at the ocular surface. While effective in treating DES, 5% (81.2 mM) lifitegrast has low drug utilization and elicits off-target effects. Here we engineer contact lenses to release therapeutically relevant doses of lifitegrast to every tear film for up to 10-hours. Lifitegrast is coupled to the polymer of the soft hydrogel lens via a photolabile (caged) crosslinker. Exposures of the lens to the 400-430 nm wavelengths of indoor daylight excite the caged crosslinker molecules and trigger a bond-cleavage reaction that releases authentic lifitegrast passively to the tear film. The photoproduct of the reaction remains chemically linked to the polymer of the single-use lens. Our studies show that passive exposures of the lens to indoor light would generate an average of 990 nM lifitegrast to every tear film in a zero-order reaction for up to 10-hours. This concentration exceeds the Kd for the interaction between ICAM-1 and LFA-1 by ~330-fold and would sustain inhibition of inflammatory responses at the ocular surface. The amount of lifitegrast released from the lens increases during exposures to outdoor sunlight. Over a 10-hour exposure to indoor light, a single lens would release 0.44% of the lifitegrast present in two drops of commercial 5% lifitegrast. Compared to tear-drop approaches, our engineered lenses would sustain the passive delivery of therapeutically relevant doses of lifitegrast over a longer period, and exhibit improved drug utilization at a lower cost. Our technology could easily be integrated into daily-use contact lenses in order to prevent inflammation at the ocular surface, dry-eye and contact lens-mediated discomfort.

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“…14 Therefore, we postulated that a small molecule LFA-1/ICAM-1 antagonist could offer a targeted T-cell antagonism with improved patient tolerability for such a chronic ocular disease. Recently, we have described the discovery of a series of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists, 15,16 which were shown to bind the I-domain of the CD11a subunit of LFA-1 and serve as direct competitive antagonists of LFA-1 binding to ICAM-1. 17,18 To our knowledge, most of the marketed ophthalmic solutions resulted from the repurposing of the drugs developed for nonocular indications.…”

mentioning

confidence: 99%

“…15,16 To address this serum shift issue, 1b (entry 2) bearing a 2-methylsulfonylfur-5-yl moiety, was identified. Additionally, a benzofur-6-yl "left-wing" residue (1c, entry 3) was found to be superior to a 4-chlorophenyl moiety (1b, entry 2) in retaining the potency in the presence of HS.…”

mentioning

confidence: 99%

Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye

Zhong

Gadek²,

Bui

et al. 2012

ACS Med. Chem. Lett.

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LFA-1/ICAM-1 interaction is essential in support of inflammatory and specific T-cell regulated immune responses by mediating cell adhesion, leukocyte extravasation, migration, antigen presentation, formation of immunological synapse, and augmentation of T-cell receptor signaling. The increase of ICAM-1 expression levels in conjunctival epithelial cells and acinar cells was observed in animal models and patients diagnosed with dry eye. Therefore, it has been hypothesized that small molecule LFA-1/ICAM-1 antagonists could be an effective topical treatment for dry eye. In this letter, we describe the discovery of a potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonist (SAR 1118) and its development as an ophthalmic solution for treating dry eye.

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Discovery of tetrahydroisoquinoline (THIQ) derivatives as potent and orally bioavailable LFA-1/ICAM-1 antagonists

Cited by 14 publications

References 41 publications

Design, synthesis, and LFA-1/ICAM-1 antagonist activity evaluation of Lifitegrast analogues

Design, synthesis, and LFA-1/ICAM-1 antagonist activity evaluation of Lifitegrast analogues

An Engineered Contact Lens for Passive and Sustained Release of Lifitegrast, an Anti-Dry Eye Syndrome Drug

Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye

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