Tuning the Metabolic Stability of Visual Cycle Modulators through Modification of an RPE65 Recognition Motif.
Publication Type:
Journal ArticleSource:
J Med Chem, Volume 66, Issue 12, p.8140-8158 (2023)Keywords:
Eye Proteins, Phenyl Ethers, Propanolamines, Retinaldehyde, Retinoids, Vision, OcularAbstract:
<p>In the eye, the isomerization of all--retinal to 11--retinal is accomplished by a metabolic pathway termed the visual cycle that is critical for vision. RPE65 is the essential - 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 and 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.</p>