Rational Alteration of Pharmacokinetics of Chiral Fluorinated and Deuterated Derivatives of Emixustat for Retinal Therapy

Eliav Blum, Jianye Zhang, Jordan Zaluski, David E. Einstein, Edward E. Korshin, Adam Kubas, Arie Gruzman, Gregory P. Tochtrop, Philip D. Kiser, Krzysztof Palczewski

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Recycling of all-trans-retinal to 11-cis-retinal through the visual cycle is a fundamental metabolic pathway in the eye. A potent retinoid isomerase (RPE65) inhibitor, (R)-emixustat, has been developed and tested in several clinical trials; however, it has not received regulatory approval for use in any specific retinopathy. Rapid clearance of this drug presents challenges to maintaining concentrations in eyes within a therapeutic window. To address this pharmacokinetic inadequacy, we rationally designed and synthesized a series of emixustat derivatives with strategically placed fluorine and deuterium atoms to slow down the key metabolic transformations known for emixustat. Crystal structures and quantum chemical analysis of RPE65 in complex with the most potent emixustat derivatives revealed the structural and electronic bases for how fluoro substituents can be favorably accommodated within the active site pocket of RPE65. We found a close (∼3.0 Å) F−π interaction that is predicted to contribute ∼2.4 kcal/mol to the overall binding energy.

Original languageEnglish
Pages (from-to)8287-8302
Number of pages16
JournalJournal of Medicinal Chemistry
Issue number12
StatePublished - 24 Jun 2021

Bibliographical note

Funding Information:
This study was supported by a Bar-Ilan University new faculty grant (to A.G.). K.P. is the Irving H. Leopold Chair of Ophthalmology at the Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine. This research was supported in part by grants to K.P. from the National Institutes of Health (NIH) (EY009339, EY027283, and EY030873); to P.D.K. from the U.S. Department of Veterans Affairs (I01BX004939); and to G.P.T. from the National Science Foundation (NSF-CHE Award no. 1904530) and the Department of Defense (DOD-CDMRP award no. W81XWH-16-1-0699). The authors also acknowledge support from an RPB unrestricted grant to the Department of Ophthalmology, University of California, Irvine. The authors also thank the Interdisciplinary Center for Mathematical and Computational Modeling in Warsaw, Poland, under grant GB79-5, for granting access to high-performance computing resources.

Publisher Copyright:
© 2021 American Chemical Society


Dive into the research topics of 'Rational Alteration of Pharmacokinetics of Chiral Fluorinated and Deuterated Derivatives of Emixustat for Retinal Therapy'. Together they form a unique fingerprint.

Cite this