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Publication Abstract from PubMed

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 gamma-amino-alpha-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.

Tuning the Metabolic Stability of Visual Cycle Modulators through Modification of an RPE65 Recognition Motif.,Bassetto M, Zaluski J, Li B, Zhang J, Badiee M, Kiser PD, Tochtrop GP J Med Chem. 2023 Jun 22;66(12):8140-8158. doi: 10.1021/acs.jmedchem.3c00461. Epub , 2023 Jun 6. PMID:37279401^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.