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

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.

Rational Alteration of Pharmacokinetics of Chiral Fluorinated and Deuterated Derivatives of Emixustat for Retinal Therapy.

Recycling of all--retinal to 11--retinal through the visual cycle is a fundamental metabolic pathway in the eye. A potent retinoid isomerase (RPE65) inhibitor, ()-emixustat, has been developed and tested in several clinical trials; however, it has not received regulatory approval for use in any specific retinopathy. Rapid clearance of this drug presents challenges to maintaining concentrations in eyes within a therapeutic window.