Emixustat is a small molecule notable for its establishment of a new class of compounds known as visual cycle modulators (VCMs). Formulated as the

hydrochloride In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternative na ...

salt Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quantitie ...

, emixustat hydrochloride, it is the first synthetic medicinal compound shown to affect retinal disease processes when taken by mouth. Emixustat was invented by the British-American chemist, Ian L. Scott, and is currently in Phase 3 trials for dry,

age-related macular degeneration Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, som ...

(AMD). The compound is also being investigated as a potential therapy for proliferative

diabetic retinopathy Diabetic retinopathy (also known as diabetic eye disease), is a medical condition in which damage occurs to the retina due to diabetes mellitus. It is a leading cause of blindness in developed countries. Diabetic retinopathy affects up to 80 perc ...

, diabetic macular edema and

Stargardt disease Stargardt disease is the most common inherited single-gene retinal disease. In terms of the first description of the disease, it follows an autosomal recessive inheritance pattern, which has been later linked to bi-allelic ABCA4 gene variants (S ...

. In 2008, Acucela Inc. partnered with Otsuka Pharmaceutical Company for the development of emixustat (ACU-4429) in an agreement totaling $263 million in cash and milestone payments. Emixustat hydrochloride is a non-retinoid small molecule inhibitor of

RPE65 Retinal pigment epithelium-specific 65 kDa protein, also known as retinoid isomerohydrolase, is an enzyme of the vertebrate visual cycle that is encoded in humans by the ''RPE65'' gene. RPE65 is expressed in the retinal pigment epithelium (RPE, a ...

(retinal pigment epithelium-specific 65 kDa protein, also known as retinoid isomerohydrolase). It is thought to reduce visual chromophore biosynthesis and prevent the accumulation of toxic retinal byproducts.

Mechanism of action

A significant factor in the pathogenesis of age-related macular degeneration (AMD) is thought to be the toxic byproduct, N-retinylidene-N-retinylethanolamine (A2E). A2E is a major chromophore in lipofuscin and causes singlet oxygen production when exposed to high-energy light. A2E is formed from the release of all-trans-retinol within the outer segment disks of human photoreceptors.

All-trans-retinol is an important component in the Visual Cycle, the mechanism by which light energy is converted into electrical energy within the eye. In the

visual cycle The visual cycle is a process in the retina that replenishes the molecule retinal for its use in vision. Retinal is the chromophore of most visual opsins, meaning it captures the photons to begin the phototransduction cascade. When the proton is ...

, exposure to light causes 11-cis-retinal to isomerize to all-trans-retinal (as part of the

rhodopsin Rhodopsin, also known as visual purple, is a protein encoded by the RHO gene and a G-protein-coupled receptor (GPCR). It is the opsin of the rod cells in the retina and a light-sensitive receptor protein that triggers visual phototransduction ...

complex). The isomerisation results in the release of chemical energy, which is processed into an electrical signal (by a series of different cells) that is transmitted to the brain. The all-trans-

retinal Retinal (also known as retinaldehyde) is a polyene chromophore. Retinal, bound to proteins called opsins, is the chemical basis of visual phototransduction, the light-detection stage of visual perception (vision). Some microorganisms use retin ...

is released from

opsin Animal opsins are G-protein-coupled receptors and a group of proteins made light-sensitive via a chromophore, typically retinal. When bound to retinal, opsins become Retinylidene proteins, but are usually still called opsins regardless. Most pro ...

, reduced to all-trans-retinol, then transported from the photoreceptor cells back to the RPE cells, where it is stored for recycling and future use as retinol palmitate. The transportation of all-trans-retinal back to RPE cells is not 100% efficient, and a small amount of all-trans-retinal can escape. This condenses with membrane-bound ethanolamine to form a Schiff's base. A second molecule of all-trans-retinal reacts with the Schiff's base and forms A2E. The formation of A2E is largely associated with the rod photoreceptor cells. These cells account for approximately 95% of human photoreceptors, and turn over cis to trans retinol constantly under normal lighting conditions. Emixustat hydrochloride is a synthetic small molecule non-retinoid designed to stop the Visual Cycle by inhibiting the formation of 11-cis-retinal. Stored all-trans-retinyl palmitate is simultaneously hydrolysed and isomerised to 11-cis-retinol by RPE-65. The 11-cis-retinol is oxidized to 11-cis retinal and transported to photoreceptor cells where it binds to opsin to form rhodopsin. Emixustat hydrochloride binds to RPE-65 and prevents the isomerohydrolase reaction. Without 11-cis-retinal, the rod photoreceptor cells no longer produce all-trans-retinol and production of A2E is halted. The isomerisation of all-trans-retinol to 11-cis-retinol also plays a key role in the pathogenesis of diabetic macular edema (DME), but by a different outcome of the same mechanism. One of the consequences of diabetes is damage to blood vessels; damaged vessels are less able to carry oxygen, thus inhibiting one of the most important biological processes within the eye. Normal retinal cells require a very large amount of oxygen. When insufficient oxygen is available, vascular remodelling occurs and poorly remodelled blood vessels leak, causing edema. The conversion of all-trans-retinol to 11-cis-retinal is a very oxygen intensive process. By blocking the isomerisation of retinol, emixustat hydrochloride may decrease the oxygen demand of the retina and therefore liberate large amounts of oxygen for other processes. In a completed Phase 1a study, the drug was "well tolerated" by male and female human participants, and demonstrated dose-dependent modulation of electroretinogram (ERG) signals. A Phase II study, completed in 2015, produced a dose dependent, reversible effect on rod function consistent with emixustat's planned mechanism of action.

References

External links

* Associated patents
ianscottmolecular.com
Experimental drugs Cyclohexyl compounds Phenol ethers

Mechanism of action

See also

References

Further reading

External links