Tuning the Metabolic Stability of Visual Cycle Modulators through Modification of an RPE65 Recognition Motif

  • J Med Chem. 2023 Jun 22;66(12):8140-8158. doi: 10.1021/acs.jmedchem.3c00461.
Marco Bassetto  1  2  3 ,  Jordan Zaluski  4 ,  Bowen Li  4 ,  Jianye Zhang  2 ,  Mohsen Badiee  4 ,  Philip D Kiser  1  2  5  3 ,  Gregory P Tochtrop  4
Affiliations
  • 1. Department of Physiology and Biophysics, School of Medicine, University of California - Irvine, Irvine, California 92697, United States.
  • 2. Department of Ophthalmology, Gavin Herbert Eye Institute, Center for Translational Vision Research, School of Medicine, University of California - Irvine, Irvine, California 92697, United States.
  • 3. Research Service, VA Long Beach Healthcare System, Long Beach, California 90822, United States.
  • 4. Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States.
  • 5. Department of Clinical Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University of California - Irvine, Irvine, California 92697, United States.
PMID: 37279401 DOI: 10.1021/acs.jmedchem.3c00461
Abstract

In the eye, the isomerization of all-trans-retinal to 11-cis-retinal is accomplished by a metabolic pathway termed the visual cycle that is critical for vision. RPE65 is the essential trans-cis isomerase of this pathway. Emixustat, a retinoid-mimetic RPE65 inhibitor, was developed as a therapeutic visual cycle modulator and used for the treatment of retinopathies. However, pharmacokinetic liabilities limit its further development including: (1) metabolic deamination of the γ-amino-α-aryl alcohol, which mediates targeted RPE65 inhibition, and (2) unwanted long-lasting RPE65 inhibition. We sought to address these issues by more broadly defining the structure-activity relationships of the RPE65 recognition motif via the synthesis of a family of novel derivatives, which were tested in vitro and in vivo for RPE65 inhibition. We identified a potent secondary amine derivative with resistance to deamination and preserved RPE65 inhibitory activity. Our data provide insights into activity-preserving modifications of the emixustat molecule that can be employed to tune its pharmacological properties.

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