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

  • ACS Med Chem Lett. 2012 Jan 31;3(3):203-6. doi: 10.1021/ml2002482.
Min Zhong  1 ,  Thomas R Gadek  2 ,  Minna Bui  1 ,  Wang Shen  1 ,  John Burnier  2 ,  Kenneth J Barr  1 ,  Emily J Hanan  1 ,  Johan D Oslob  1 ,  Chul H Yu  1 ,  Jiang Zhu  1 ,  Michelle R Arkin  1 ,  Marc J Evanchik  1 ,  W Mike Flanagan  1 ,  Ute Hoch  1 ,  Jennifer Hyde  1 ,  Saileta Prabhu  1 ,  Jeffrey A Silverman  1 ,  Jasmin Wright  1
Affiliations
  • 1. Sunesis Pharmaceuticals, Inc. , 395 Oyster Point Boulevard, Suite 400, South San Francisco, California 94080, United States.
  • 2. SARcode Bioscience, Inc. , 1000 Marina Boulevard, Suite 250, Brisbane, California 94005, United States.
PMID: 24900456 DOI: 10.1021/ml2002482
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.

Keywords
LFA-1/ICAM-1 antagonist; SAR 1118; dry eye; ophthalmic solution; tetrahydroisoquinoline derivative.