Emixustat - CAS 1141777-14-1
Category: Inhibitor
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Molecular Formula:
Molecular Weight:
Emixustat, a novel visual cycle modulator, is a nonretinoid compound that directly inhibits RPE65, but does not bind to RAR/
RXR retinoid receptors or antagonize retinoid binding proteins.
Brife Description:
An inhibitor of the visual cycle isomerase (IC50= 4.4 nM in vitro)
(1R)-3-amino-1-[3-(cyclohexylmethoxy)phenyl]propan-1-ol; ACU-4429; emixustat
DMSO: ≥ 43 mg/mL
Store in a cool and dry place (or refer to the Certificate of Analysis).
Boiling Point:
430.9±40.0 ℃ at 760 Torr
1.065±0.06 g/cm3
Canonical SMILES:
1.Molecular pharmacodynamics of emixustat in protection against retinal degeneration.
Zhang J;Kiser PD;Badiee M;Palczewska G;Dong Z;Golczak M;Tochtrop GP;Palczewski K J Clin Invest. 2015 Jul 1;125(7):2781-94. doi: 10.1172/JCI80950. Epub 2015 Jun 15.
Emixustat is a visual cycle modulator that has entered clinical trials as a treatment for age-related macular degeneration (AMD). This molecule has been proposed to inhibit the visual cycle isomerase RPE65, thereby slowing regeneration of 11-cis-retinal and reducing production of retinaldehyde condensation byproducts that may be involved in AMD pathology. Previously, we reported that all-trans-retinal (atRAL) is directly cytotoxic and that certain primary amine compounds that transiently sequester atRAL via Schiff base formation ameliorate retinal degeneration. Here, we have shown that emixustat stereoselectively inhibits RPE65 by direct active site binding. However, we detected the presence of emixustat-atRAL Schiff base conjugates, indicating that emixustat also acts as a retinal scavenger, which may contribute to its therapeutic effects. Using agents that lack either RPE65 inhibitory activity or the capacity to sequester atRAL, we assessed the relative importance of these 2 modes of action in protection against retinal phototoxicity in mice. The atRAL sequestrant QEA-B-001-NH2 conferred protection against phototoxicity without inhibiting RPE65, whereas an emixustat derivative incapable of atRAL sequestration was minimally protective, despite direct inhibition of RPE65.
2.Retinoid isomerase inhibitors impair but do not block mammalian cone photoreceptor function.
Kiser PD;Zhang J;Sharma A;Angueyra JM;Kolesnikov AV;Badiee M;Tochtrop GP;Kinoshita J;Peachey NS;Li W;Kefalov VJ;Palczewski K J Gen Physiol. 2018 Apr 2;150(4):571-590. doi: 10.1085/jgp.201711815. Epub 2018 Mar 2.
Visual function in vertebrates critically depends on the continuous regeneration of visual pigments in rod and cone photoreceptors. RPE65 is a well-established retinoid isomerase in the pigment epithelium that regenerates rhodopsin during the rod visual cycle; however, its contribution to the regeneration of cone pigments remains obscure. In this study, we use potent and selective RPE65 inhibitors in rod- and cone-dominant animal models to discern the role of this enzyme in cone-mediated vision. We confirm that retinylamine and emixustat-family compounds selectively inhibit RPE65 over DES1, the putative retinoid isomerase of the intraretinal visual cycle. In vivo and ex vivo electroretinography experiments in ;Gnat1;-/-; mice demonstrate that acute administration of RPE65 inhibitors after a bleach suppresses the late, slow phase of cone dark adaptation without affecting the initial rapid portion, which reflects intraretinal visual cycle function. Acute administration of these compounds does not affect the light sensitivity of cone photoreceptors in mice during extended exposure to background light, but does slow all phases of subsequent dark recovery. We also show that cone function is only partially suppressed in cone-dominant ground squirrels and wild-type mice by multiday administration of an RPE65 inhibitor despite profound blockade of RPE65 activity.
3.Disposition, profiling and identification of emixustat and its metabolites in humans.
Fitzsimmons ME;Sun G;Kuksa V;Reid MJ Xenobiotica. 2018 Jun;48(6):592-604. doi: 10.1080/00498254.2017.1350889. Epub 2017 Jul 28.
1. Emixustat is a small molecule that potently inhibits retinal pigment epithelium 65 isomerohydrolase. Emixustat is in clinical development for the treatment of various retinopathies (i.e. Stargardt disease and diabetic retinopathy). 2. A human absorption, distribution, metabolism, and excretion (ADME) study was conducted with a single dose of [;14;C]-emixustat in healthy male subjects. Total ;14;C content in plasma, urine, and faeces was determined using accelerator mass spectrometry (AMS), and metabolic profiles in pooled plasma and urine were investigated by both HPLC-AMS and 2D LC-MS/MS. 3. After a single, oral 40-mg dose of [;14;C]-emixustat, recovery of total ;14;C was nearly complete within 24 h. Urine was the major route of ;14;C elimination; accounting for > 90% of the administered dose. 4. Biotransformation of emixustat occurred primarily at two structural moieties; oxidation of the cyclohexyl moiety and oxidative deamination of the 3R-hydroxypropylamine, both independently and in combination to produce secondary metabolites. Metabolite profiling in pooled plasma samples identified 3 major metabolites: ACU-5124, ACU-5116 and ACU-5149, accounting for 29.0%, 11.5%, and 10.6% of total ;14;C, respectively.
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CAS 1141777-14-1 Emixustat

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