Rationally Designed, Short-Acting RPE65 Inhibitors for Visual Cycle-Associated Retinopathies

The visual cycle is a metabolic pathway essential for
visual function.
The bisretinoid byproducts of this pathway can induce retinal toxicity,
as occurs in Stargardt disease type 1 (STGD1). Emixustat, which inhibits
bisretinoid production, is a visual cycle modulator (VCM) that targets
RPE65. However, it causes visual impairment due to its unfavorable
duration of action. Here, we report ester-containing analogs of emixustat
that are susceptible to hydrolytic clearance and function as short-acting
VCMs. We show that the esterase-mediated metabolism of these compounds
can be tuned while maintaining high-affinity RPE65 targeting. Compounds 6 (EYE-002) and 7 (EYE-003) containing diethyl
acetate and valproate esters, respectively, allowed faster recovery
of visual cycle function compared to emixustat. These molecules protected
against retinal degeneration in mouse models of photic retinopathy
and STGD1. These data demonstrate that shorter attenuation of the
visual cycle can therapeutically intervene in retinal diseases with
fewer visual side effects compared to emixustat.