Omaveloxolone

Omaveloxolone
Clinical data
Routes of; administration	Oral, Topical (Dermal), Topical (Ophthalmic)
ATC code	none;
Legal status
Legal status	Investigational;
Identifiers
	IUPAC name N-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-1 1-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b- octadecahydropicen-4a-yl)-2,2-difluoropropanamide;
CAS Number	1474034-05-3 ;
PubChem CID	71811910;
IUPHAR/BPS	7573;
UNII	G69Z98951Q;
CompTox Dashboard (EPA)	DTXSID101138251 ;
Chemical and physical data
Formula	C33H44F2N2O3
Molar mass	554.33 g/mol g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C4C(\C#N)=C/[C@@]5(/C3=C/C(=O)[C@H]2[C@](CC[C@@]1(C(=O)OC)CCC(C)(C)C[C@H]12)(C)[C@]3(C)CC[C@H]5C4(C)C)C;
	InChI InChI=1S/C32H43NO4/c1-27(2)11-13-32(26(36)37-8)14-12-31(7)24(20(32)17-27)21(34)15-23-29(5)16-19(18-33)25(35)28(3,4)22(29)9-10-30(23,31)6/h15-16,20,22,24H,9-14,17H2,1-8H3/t20-,22-,24-,29-,30+,31+,32-/m0/s1 ; Key:WPTTVJLTNAWYAO-KPOXMGGZSA-N ;
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RTA 408 is a second generation member of the synthetic oleanane triterpenoid compounds and currently in clinical development by Reata Pharmaceuticals. Preclinical studies have demonstrated that RTA 408 possesses antioxidative and anti-inflammatory activities^[1]^[2] and the ability to improve mitochondrial bioenergetics.^[3] RTA 408 is currently under clinical investigation for a variety of indications, including Friedreich’s ataxia, mitochondrial myopathies, immunooncology, and prevention of corneal endothelial cell loss following cataract surgery.

Mechanism of action

The effects of RTA 408 and related synthetic triterpenoid compounds have been documented in over 200 peer-reviewed scientific manuscripts.^[4] The mechanism of action of RTA 408 and its related compounds has been demonstrated to be through a combination of activation of the antioxidative transcription factor Nrf2 and inhibition of the pro-inflammatory transcription factor NF-κB.^[1]

Nrf2 transcriptionally regulates multiple genes that play both direct and indirect roles in producing antioxidative potential and the production of cellular energy (i.e., adenosine triphosphate or ATP) within the mitochondria. Consequently, unlike exogenously administered antioxidants (e.g., vitamin E or Coenzyme Q10), which provide a specific and finite antioxidative potential, RTA 408, through Nrf2, broadly activates intracellular and mitochondrial antioxidative pathways, in addition to pathways that may directly increase mitochondrial biogenesis (such as PGC1α) and bioenergetics.^[3]

References

^ ^a ^b Reisman SA, Lee CY, Meyer CJ, Proksch JW, Ward KW (Jul 2014). "Topical application of the synthetic triterpenoid RTA 408 activates Nrf2 and induces cytoprotective genes in rat skin". Archives of Dermatological Research. 306 (5): 447–54. doi:10.1007/s00403-013-1433-7. PMID 24362512.
^ Reisman SA, Lee CY, Meyer CJ, Proksch JW, Sonis ST, Ward KW (May 2014). "Topical application of the synthetic triterpenoid RTA 408 protects mice from radiation-induced dermatitis". Radiation Research. 181 (5): 512–20. doi:10.1667/RR13578.1. PMID 24720753.
^ ^a ^b Neymotin A, Calingasan NY, Wille E, Naseri N, Petri S, Damiano M, Liby KT, Risingsong R, Sporn M, Beal MF, Kiaei M (Jul 2011). "Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis". Free Radical Biology & Medicine. 51 (1): 88–96. doi:10.1016/j.freeradbiomed.2011.03.027. PMC 3109235. PMID 21457778.
^ "Pubmed Search". April 15, 2015. Retrieved April 15, 2015.

[:0-1] Reisman SA, Lee CY, Meyer CJ, Proksch JW, Ward KW (Jul 2014). "Topical application of the synthetic triterpenoid RTA 408 activates Nrf2 and induces cytoprotective genes in rat skin". Archives of Dermatological Research. 306 (5): 447–54. doi:10.1007/s00403-013-1433-7. PMID 24362512.

[Reisman_2014-2] Reisman SA, Lee CY, Meyer CJ, Proksch JW, Sonis ST, Ward KW (May 2014). "Topical application of the synthetic triterpenoid RTA 408 protects mice from radiation-induced dermatitis". Radiation Research. 181 (5): 512–20. doi:10.1667/RR13578.1. PMID 24720753.

[:2-3] Neymotin A, Calingasan NY, Wille E, Naseri N, Petri S, Damiano M, Liby KT, Risingsong R, Sporn M, Beal MF, Kiaei M (Jul 2011). "Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis". Free Radical Biology & Medicine. 51 (1): 88–96. doi:10.1016/j.freeradbiomed.2011.03.027. PMC 3109235. PMID 21457778.

[4] "Pubmed Search". April 15, 2015. Retrieved April 15, 2015.

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