Rational Tuning of Visual Cycle Modulator Pharmacodynamics

Area of Science:

• Biochemistry
• Ophthalmology
• Drug Discovery

Background:

• Modulators of the visual cycle are investigated for treating retinal disorders.
• Inhibiting RPE65 (retinoid isomerase) aims to reduce toxic retinal conjugate formation.
• Some agents also sequester retinaldehyde via Schiff base adducts, offering retinal protection.

Purpose of the Study:

• To guide the design of retinaldehyde-sequestering agents using the RPE65-emixustat crystal structure.
• To explore agents with varying degrees of RPE65 inhibitory activity and retinal sequestration capabilities.

Main Methods:

• Synthesized emixustat derivatives with modifications to the central phenyl ring and terminal 6-membered ring.
• Assessed in vitro retinoid isomerase inhibitory activity.
• Evaluated in vivo visual cycle suppression, retinal distribution, Schiff base adduct formation, and retinal phototoxicity protection.

Main Results:

• Isopropyl group addition reduced in vitro RPE65 inhibition.
• Branched moieties on the terminal ring enhanced RPE65 inhibition.
• Isopropyl derivatives showed visual cycle suppression in vivo, but less potently than high-affinity inhibitors.
• Agents distributed to the retina and formed Schiff base adducts.
• Most agents conferred photoprotection, indicating dual therapeutic mechanisms.

Conclusions:

• Drug design can modulate RPE65 inhibition and retinaldehyde sequestration.
• Both direct RPE65 inhibition and retinal sequestration are relevant therapeutic mechanisms for retinal disorders.
• MB-007 was an exception in conferring protection, suggesting nuanced structure-activity relationships.