2. Academic Validation
  3. Rationally Designed, Short-Acting RPE65 Inhibitors for Visual Cycle-Associated Retinopathies

Rationally Designed, Short-Acting RPE65 Inhibitors for Visual Cycle-Associated Retinopathies

  • J Med Chem. 2025 Aug 28;68(16):17638-17652. doi: 10.1021/acs.jmedchem.5c01353.
Marco Bassetto 1 2 3,  Yulun Hu 4,  Bowen Li 4,  Xiuyuan Chen 4,  Vivek Saraswat 4,  Francisco Damacio 5,  Roman Smidak 3,  Krzysztof Palczewski 1 3 6 7,  Gregory P Tochtrop 4,  Philip D Kiser 1 2 3 5
Affiliations

Affiliations

  • 1 Department of Physiology and Biophysics, School of Medicine, University of California Irvine, Irvine, California 92697, United States.
  • 2 Research Service, Tibor Rubin VA Long Beach Medical Center, Long Beach, California 90822, United States.
  • 3 Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology, University of Irvine, Irvine, California 92697, 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.
  • 6 Department of Chemistry, University of California Irvine, Irvine, California 92697, United States.
  • 7 Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California 92697, United States.
PMID: 40764714 DOI: 10.1021/acs.jmedchem.5c01353
Abstract

The visual cycle is a metabolic pathway essential for visual function. The bisretinoid byproducts of this pathway can induce retinal toxicity, as occurs in Stargardt disease type 1 (STGD1). Emixustat, which inhibits bisretinoid production, is a visual cycle modulator (VCM) that targets RPE65. However, it causes visual impairment due to its unfavorable duration of action. Here, we report ester-containing analogs of emixustat that are susceptible to hydrolytic clearance and function as short-acting VCMs. We show that the esterase-mediated metabolism of these compounds can be tuned while maintaining high-affinity RPE65 targeting. Compounds 6 (EYE-002) and 7 (EYE-003) containing diethyl acetate and valproate esters, respectively, allowed faster recovery of visual cycle function compared to emixustat. These molecules protected against retinal degeneration in mouse models of photic retinopathy and STGD1. These data demonstrate that shorter attenuation of the visual cycle can therapeutically intervene in retinal diseases with fewer visual side effects compared to emixustat.

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