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

Recycling of all-trans-retinal to 11-cis-retinal through the visual cycle
is a fundamental metabolic pathway
in the eye. A potent retinoid isomerase (RPE65) inhibitor, (R)-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.
To address this pharmacokinetic inadequacy, we rationally designed
and synthesized a series of emixustat derivatives with strategically
placed fluorine and deuterium atoms to slow down the key metabolic
transformations known for emixustat. Crystal structures and quantum
chemical analysis of RPE65 in complex with the most potent emixustat
derivatives revealed the structural and electronic bases for how fluoro
substituents can be favorably accommodated within the active site
pocket of RPE65. We found a close (∼3.0 Å) F−π
interaction that is predicted to contribute ∼2.4 kcal/mol to
the overall binding energy.