Rational Tuning of Visual Cycle Modulator Pharmacodynamics

Abstract

Modulators of the visual cycle have been developed for treatment of various retinal disorders. These agents were designed to inhibit retinoid isomerase [retinal pigment epithelium-specific 65 kDa protein (RPE65)], the rate-limiting enzyme of the visual cycle, based on the idea that attenuation of visual pigment regeneration could reduce formation of toxic retinal conjugates. Of these agents, certain ones that contain primary amine groups can also reversibly form retinaldehyde Schiff base adducts, which contributes to their retinal protective activity. Direct inhibition of RPE65 as a therapeutic strategy is complicated by adverse effects resulting from slowed chromophore regeneration, whereas effective retinal sequestration can require high drug doses with potential off-target effects. We hypothesized that the RPE65-emixustat crystal structure could help guide the design of retinaldehydesequestering agents with varying degrees of RPE65 inhibitory activity. We found that addition of an isopropyl group to the central phenyl ring of emixustat and related compounds resulted in agents effectively lacking in vitro retinoid isomerase inhibitory activity, whereas substitution of the terminal 6-membered ring with branched moieties capable of stronger RPE65 interaction potentiated inhibition. The isopropyl derivative series produced discernible visual cycle suppression in vivo, albeit much less potently than compounds with a high affinity for the RPE65 active site. These agents were distributed into the retina and formed Schiff base adducts with retinaldehyde. Except for one compound [3-amino-1-(3-isopropyl-5-((2,6,6-trimethylcyclohex-1-en-1-yl)methoxy)phenyl)propan-1-ol (MB-007)], these agents conferred protection against retinal phototoxicity, suggesting that both direct RPE65 inhibition and retinal sequestration are mechanisms of potential therapeutic relevance.

Rhythmic Regulation of Photoreceptor and RPE Genes Important for Vision and Genetically Associated With Severe Retinal Diseases

“… 51 – 53 Interestingly, the release of retinaldehydes during light exposure/daytime and thus the requirement for protection depends on Rpe65 activity. 54 , 55 Therefore, upregulation of Rdh12 during the daytime may be necessary to compensate for an Rpe65- dependent increase in retinaldehyde release.…”

Pathways and disease-causing alterations in visual chromophore production for vertebrate vision

“…Emixustat (Figure 2 and Movie 2) is approximately ten times more potent than retinylamine in vitro (Zhang et al, 2015), is orally bioavailable (Kubota et al, 2014), and exerts specific effects on in vivo visual cycle activity as demonstrated in Phase 1 and 2 clinical trials (Dugel et al, 2015). It was shown that the potency of emixustat can be further improved by substitutions at the cyclohexyl moiety, for example in the molecule MB-004 (Kiser et al, 2017). Unfortunately, emixustat failed to demonstrate efficacy in the treatment of geographic atrophy as assessed in a large Phase 3 randomized, double-blind, placebocontrolled trial (Rosenfeld et al, 2018).…”

“…Interestingly, retinylamine/emixustat family molecules exhibit a second mechanism of action involving the direct sequestration of retinal released from bleached visual pigments, and this action plays a key role in the ability of these molecules to protect against light-induced retinal degeneration (Maeda et al, 2009;Zhang et al, 2015). Efforts are currently underway to develop retina-targeted retinaldehyde traps for treatment of diseases associated with formation of toxic retinaldehyde adducts (Kiser et al, 2017;Maeda et al, 2012).…”

Mechanistical retinal drug targets and challenges

“…enzyme of the visual cycle, based on the idea that an attenuation of visual pigment regeneration could reduce the formation of toxic retinal conjugates [19,20].…”