title: Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye.
abstract: 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.
authors.affiliation: Sunesis Pharmaceuticals, Inc. , 395 Oyster Point Boulevard, Suite 400, South San Francisco, California 94080, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Zhong
authors.affiliation: SARcode Bioscience, Inc. , 1000 Marina Boulevard, Suite 250, Brisbane, California 94005, United States.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Gadek
authors.affiliation: Sunesis Pharmaceuticals, Inc. , 395 Oyster Point Boulevard, Suite 400, South San Francisco, California 94080, United States.
authors.forename: Minna
authors.initials: M
authors.lastname: Bui
authors.affiliation: Sunesis Pharmaceuticals, Inc. , 395 Oyster Point Boulevard, Suite 400, South San Francisco, California 94080, United States.
authors.forename: Wang
authors.initials: W
authors.lastname: Shen
authors.affiliation: SARcode Bioscience, Inc. , 1000 Marina Boulevard, Suite 250, Brisbane, California 94005, United States.
authors.forename: John
authors.initials: J
authors.lastname: Burnier
authors.affiliation: Sunesis Pharmaceuticals, Inc. , 395 Oyster Point Boulevard, Suite 400, South San Francisco, California 94080, United States.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Barr
authors.affiliation: Sunesis Pharmaceuticals, Inc. , 395 Oyster Point Boulevard, Suite 400, South San Francisco, California 94080, United States.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Hanan
authors.affiliation: Sunesis Pharmaceuticals, Inc. , 395 Oyster Point Boulevard, Suite 400, South San Francisco, California 94080, United States.
authors.forename: Johan D
authors.initials: JD
authors.lastname: Oslob
authors.affiliation: Sunesis Pharmaceuticals, Inc. , 395 Oyster Point Boulevard, Suite 400, South San Francisco, California 94080, United States.
authors.forename: Chul H
authors.initials: CH
authors.lastname: Yu
authors.affiliation: Sunesis Pharmaceuticals, Inc. , 395 Oyster Point Boulevard, Suite 400, South San Francisco, California 94080, United States.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Sunesis Pharmaceuticals, Inc. , 395 Oyster Point Boulevard, Suite 400, South San Francisco, California 94080, United States.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
authors.affiliation: Sunesis Pharmaceuticals, Inc. , 395 Oyster Point Boulevard, Suite 400, South San Francisco, California 94080, United States.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Evanchik
authors.affiliation: Sunesis Pharmaceuticals, Inc. , 395 Oyster Point Boulevard, Suite 400, South San Francisco, California 94080, United States.
authors.forename: W Mike
authors.initials: WM
authors.lastname: Flanagan
authors.affiliation: Sunesis Pharmaceuticals, Inc. , 395 Oyster Point Boulevard, Suite 400, South San Francisco, California 94080, United States.
authors.forename: Ute
authors.initials: U
authors.lastname: Hoch
authors.affiliation: Sunesis Pharmaceuticals, Inc. , 395 Oyster Point Boulevard, Suite 400, South San Francisco, California 94080, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hyde
authors.affiliation: Sunesis Pharmaceuticals, Inc. , 395 Oyster Point Boulevard, Suite 400, South San Francisco, California 94080, United States.
authors.forename: Saileta
authors.initials: S
authors.lastname: Prabhu
authors.affiliation: Sunesis Pharmaceuticals, Inc. , 395 Oyster Point Boulevard, Suite 400, South San Francisco, California 94080, United States.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Silverman
authors.affiliation: Sunesis Pharmaceuticals, Inc. , 395 Oyster Point Boulevard, Suite 400, South San Francisco, California 94080, United States.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Wright
keywords: LFA-1/ICAM-1 antagonist; SAR 1118; dry eye; ophthalmic solution; tetrahydroisoquinoline derivative