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

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

University of California at Irvine

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English
Article number	127421
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	30
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2020.127421
State	Published - 15 Sep 2020

Bibliographical note

Publisher Copyright:
© 2020 Elsevier Ltd

Funding

This study was supported by a Bar-Ilan University new faculty grant (to A.G). This research was in part supported in part by grant to K.P. from the National Institutes of Health (NIH) EY009339. The authors also acknowledge support from an RPB unrestricted grant to the Department of Ophthalmology, University of California, Irvine, USA. Israel Ministry of Immigration and Integration through Kamea fellowship supported EEK (8279). We thank Dr. Huajun Yan for his help with the cell viability assay, and Mr. Steven Manch for the English editing. K. Palczewski is the Leopold Chair of Ophthalmology at the Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, USA. This study was supported by a Bar-Ilan University new faculty grant (to A.G). This research was in part supported in part by grant to K.P. from the National Institutes of Health (NIH) EY009339. The authors also acknowledge support from an RPB unrestricted grant to the Department of Ophthalmology, University of California, Irvine, USA. Israel Ministry of Immigration and Integration through Kamea fellowship supported EEK (8279). We thank Dr. Huajun Yan for his help with the cell viability assay, and Mr. Steven Manch for the English editing. K. Palczewski is the Leopold Chair of Ophthalmology at the Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, USA.

Funders	Funder number
Department of Ophthalmology
Gavin Herbert Eye Institute
Israel Ministry of Immigration and Integration	EEK (8279
University of California, Irvine, USA
National Institutes of Health
National Eye Institute	R01EY009339
Research to Prevent Blindness
University of California, Irvine
Bar-Ilan University

Keywords

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

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

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.",

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

Abstract

Bibliographical note

Funding

Keywords

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