Emixustat

Emixustat
Legal status
Legal status
  • Investigational
Identifiers
PubChem CID
ChemSpider
KEGG
Chemical and physical data
Formula C16H25NO2
Molar mass 263.38 g·mol−1
3D model (JSmol)

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 salt, emixustat hydrochloride, it is the first synthetic medicinal compound shown to affect retinal disease processes when taken by mouth.[1][2] Emixustat was invented by the British-American chemist, Ian L. Scott, and is currently in Phase 3 trials for dry, age-related macular degeneration (AMD).[3][4][5][6] The compound is also being investigated as a potential therapy for proliferative diabetic retinopathy, diabetic macular edema and Stargardt disease.[7] 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.[8]

Emixustat hydrochloride is a non-retinoid small molecule inhibitor of RPE65 (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.[9]

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).[10] 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.

Visual Cycle

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, exposure to light causes 11-cis-retinal to isomerize to all-trans-retinal (as part of the rhodopsin 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 is released from opsin, 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.[11]

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.[12]

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.[13]

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.[14]

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.[15] A Phase II study, completed in 2015, produced a dose dependent, reversible effect on rod function consistent with emixustat's planned mechanism of action.[10]

See also

References

  1. ↑ Batik C, Henry SH, Zhang Y, et al. (2015). "Visual Cycle Modulation as an Approach to Preserving Retinal Integrity". PLoS ONE. 10.5 (E0124940). doi:10.1371/journal.pone.01214940.
  2. ↑ Kubota, R; et al. (January 2013). "Safety and effect on rod function of ACU-4429, a novel small-molecule visual cycle modulator". Retina. 32 (1): 183–8. doi:10.1097/IAE.0b013e318217369e. PMID 21519291.
  3. ↑ The Wall Street Transcript, Ryo Kubota - Acucela Inc, March 20, 2006, (http://www.twst.com/interview/26482)
  4. ↑ US patent 7982071, Scott; Ian L., et al., "Alcoxy Compounds for Disease Treatment", issued 2011-July-19 http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=7982071.PN.&OS=PN/7982071&RS=PN/7982071
  5. ↑ Safety and Efficacy Assessment Treatment Trials of Emixustat Hydrochloride https://clinicaltrials.gov/ct2/show/NCT01802866
  6. ↑ http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=8,829,244.PN.&OS=PN/8,829,244&RS=PN/8,829,244
  7. ↑ Tuohy, Gearoid. "Phase II clinical study of emixustat hydrochloride for treatment of geographic atrophy shows dose-dependent effect". EURETINA. EURETINA-Brief. Retrieved 30 March 2015.
  8. ↑ Carroll, John. "Acucela inks development deal for two compounds". Fierce Biotech. Fierce Markets. Retrieved 30 March 2016.
  9. ↑ Bavik, C; Henry, SH; Zhang, Y; Mitts, K; McGinn, T; Budzynski, E; Pashko, A; Lieu, KL; Zhong, S; Blumberg, B; Kuksa, V; Orme, M; Scott, I; Fawzi, A; Kubota, R (2015). "Visual Cycle Modulation as an Approach toward Preservation of Retinal Integrity". PLoS ONE. 10: e0124940. Bibcode:2015PLoSO..1024940B. doi:10.1371/journal.pone.0124940. PMC 4430241. PMID 25970164.
  10. 1 2 Dugel, P; et al. (June 2015). "Phase II, randomized, placebo-controlled, 90-day study of emixustat hydrochloride in geographic atrophy associated with dry age-related macular degeneration". Retina. 35 (6): 1173–1183. doi:10.1097/iae.0000000000000606. PMC 4452434. PMID 25932553.
  11. ↑ Kolb, Helga. "Photoreceptors". Webvision. Moran Eye Center. Retrieved 30 March 2016.
  12. ↑ Zarbin, Marco. "Pathogenesis of Age-Related Macular Degeneration" (PDF). Medical Retina; ESASO Course Series. Institute of Ophthalmology and Visual Science-New Jersey Medical School. Retrieved 30 March 2016.
  13. ↑ US patent 8829244, Scott; Ian L., et al., "Alcoxy Compounds for Disease Treatment", issued 2014-September-9 http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=8,829,244.PN.&OS=PN/8,829,244&RS=PN/8,829,244
  14. ↑ Arden, Geoffrey. "Diabetic Retinopathy and A Novel Treatment Based On The Biophysics Of Rod Photoreceptors And Dark Adaptation by Geoffrey. B. Arden and David J. Ramsey". Webvision. Moran Eye Center. Retrieved 30 March 2016.
  15. ↑ Maldonado, Maria; et al. (November 2013). "Dry AMD: Focus on protecting the RPE". Review of Ophthalmology. Jobson Medical Information LLC. Retrieved March 2016. Check date values in: |accessdate= (help)

Further reading

  • Bavik, C; Henry, SH; Zhang, Y; Mitts, K; McGinn, T; Budzynski, E; et al. (2015). "Visual Cycle Modulation as an Approach toward Preservation of Retinal Integrity". PLoS ONE. 10 (5): e0124940. Bibcode:2015PLoSO..1024940B. doi:10.1371/journal.pone.0124940. PMC 4430241. PMID 25970164.
  • Kubota, R; Al-Fayoumi, S; Malikaarjun, S; Patil, S; Bavik, C; Chandler, JW (Mar 2014). "Phase 1 dose-ranging study of emixustat hydrochloride (ACU-4429), a novel visual cycle modulator, in healthy volunteers". Retina. 34 (3): 603–609. doi:10.1097/01.iae.0000434565.80060.f8. PMID 24056528.
  • Akula, J.D.; et al. (2010). "Visual cycle modulation in neurovascular retinopathy". Exp Eye Res. 91 (2): 153–61. doi:10.1016/j.exer.2010.04.008.
  • Radu, R.A.; et al. (2003). "Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration". Proc Natl Acad Sci U S A. 100 (8): 4742–7. Bibcode:2003PNAS..100.4742R. doi:10.1073/pnas.0737855100. PMC 153626.
  • Sieving, P.A.; et al. (2001). "Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy". Proc Natl Acad Sci U S A. 98 (4): 1835–40. doi:10.1073/pnas.041606498. PMC 29343. PMID 11172037.
  • Mata, N.L.; Weng, J.; Travis, G.H. (2000). "Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration". Proc Natl Acad Sci U S A. 97 (13): 7154–9. Bibcode:2000PNAS...97.7154M. doi:10.1073/pnas.130110497. PMC 16515. PMID 10852960.
  • Parish, C.A.; et al. (1998). "Isolation and one-step preparation of A2E and iso-A2E, fluorophores from human retinal pigment epithelium". Proc Natl Acad Sci U S A. 95 (25): 14609–13. Bibcode:1998PNAS...9514609P. doi:10.1073/pnas.95.25.14609. PMC 24497.
  • Bernstein, P.S.; Lichtman, J.R. (1986). "Rando Short-circuiting the visual cycle with retinotoxic aromatic amines". Proc Natl Acad Sci U S A. 83 (6): 1632–5. Bibcode:1986PNAS...83.1632B. doi:10.1073/pnas.83.6.1632. PMC 323137. PMID 3485289.
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