Development of chiral fluorinated alkyl derivatives of emixustat as drug candidates for the treatment of retinal degenerative diseases

Eliav Blum; Jianye Zhang; Edward Korshin; Krzysztof Palczewski; Arie Gruzman

doi:10.1016/j.bmcl.2020.127421

Development of chiral fluorinated alkyl derivatives of emixustat as drug candidates for the treatment of retinal degenerative diseases

Bioorg Med Chem Lett. 2020 Sep 15;30(18):127421. doi: 10.1016/j.bmcl.2020.127421. Epub 2020 Jul 18.

Authors

Eliav Blum¹, Jianye Zhang², Edward Korshin¹, Krzysztof Palczewski³, Arie Gruzman⁴

Affiliations

¹ Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.
² Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, CA 92697, USA.
³ Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, CA 92697, USA; Departments of Physiology and Biophysics, and Chemistry, University of California, Irvine, CA 92697, USA.
⁴ Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel. Electronic address: gruzmaa@biu.ac.il.

Abstract

The discovery of how a photon is converted into a chemical signal is one of the most important achievements in the field of vision. A key molecule in this process is the visual chromophore retinal. Several eye diseases are attributed to the abnormal metabolism of retinal in the retina and the retinal pigment epithelium. Also, the accumulation of two toxic retinal derivatives, N-retinylidene-N-retinylethanolamine and the retinal dimer, can damage the retina leading to blindness. RPE65 (Retinal pigment epithelium-specific 65 kDa protein) is one of the central enzymes that regulates the metabolism of retinal and the formation of its toxic metabolites. Its inhibition might decrease the rate of the retina's degeneration by limiting the amount of retinal and its toxic byproducts. Two RPE65 inhibitors, (R)-emixustat and (R)-MB001, were recently developed for this purpose.

Keywords: (R)-MB001; (R)-emixustat; Fluorinated alkyles; RPE65 (Retinal pigment epithelium-specific 65 kDa protein; Retinal; Retinal degeneration.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alkanes / chemistry
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology
Halogenation
Humans
Isomerism
Models, Molecular
Molecular Conformation
Pharmaceutical Preparations / chemical synthesis
Phenyl Ethers / chemical synthesis*
Phenyl Ethers / pharmacology
Propanolamines / chemical synthesis*
Propanolamines / pharmacology
Retina / metabolism
Retinal Degeneration / drug therapy*
Retinaldehyde / analogs & derivatives
Retinaldehyde / metabolism
Structure-Activity Relationship
cis-trans-Isomerases / antagonists & inhibitors*

Substances

Alkanes
Enzyme Inhibitors
Pharmaceutical Preparations
Phenyl Ethers
Propanolamines
retinal dimer
emixustat
retinoid isomerohydrolase
cis-trans-Isomerases
Retinaldehyde

Grants and funding

R01 EY009339/EY/NEI NIH HHS/United States