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

Area of Science:

• Biochemistry
• Ophthalmology
• Medicinal Chemistry

Background:

• The visual cycle in the eye is crucial for vision, involving the isomerization of all-trans-retinal to 11-cis-retinal.
• RPE65 is the key enzyme in this pathway, acting as a trans-cis isomerase.
• Emixustat, an RPE65 inhibitor, was explored for treating retinopathies but faced pharmacokinetic limitations.

Purpose of the Study:

• To address limitations of emixustat, including metabolic deamination and prolonged inhibition.
• To explore structure-activity relationships of RPE65 inhibitors by synthesizing novel derivatives.
• To identify modified RPE65 inhibitors with improved pharmacokinetic profiles.

Main Methods:

• Synthesis of a novel family of RPE65 inhibitor derivatives.
• In vitro and in vivo testing of synthesized compounds for RPE65 inhibition.
• Evaluation of metabolic stability and duration of RPE65 inhibition.

Main Results:

• Identification of a potent secondary amine derivative of emixustat.
• The new derivative demonstrated resistance to metabolic deamination.
• Preserved RPE65 inhibitory activity was observed in the novel derivative.
• Insights into modifications for tuning pharmacological properties were gained.

Conclusions:

• Novel RPE65 inhibitors with improved pharmacokinetic properties were developed.
• A secondary amine derivative offers a promising alternative to emixustat.
• These findings contribute to the development of more effective treatments for retinopathies.