Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development

Natalia Robledinos-Antón, Raquel Fernández-Ginés, Gina Manda, and Antonio Cuadrado, Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 9372182, 20 pages, 2019. doi:10.1155/2019/9372182.


Synthetic triterpenoids have been derived from the natural compound oleanolic acid to provide them with strong Michael acceptor reactivity. This is achieved mainly through the addition of enone and ciano groups to the A ring and another enone group to the C ring. Bardoxolone methyl (CDDO-Me or RTA 402) reached clinical trials for the treatment of advanced chronic kidney disease (CKD) and type 2 diabetes mellitus. Although phase II clinical trials demonstrated long-term increment in glomerular filtration, CDDO-Me was halted at phase III due to cardiovascular safety issues. A new phase II clinical trial has recently started recruiting patients with rare chronic kidney diseases to better define the safety and efficacy profiles of CDDO-Me. Currently, CDDO-Me is also under clinical study for the Alport syndrome and pulmonary hypertension. In an effort to improve the safety profile, a second-generation difluoromethyl acetamide derivative of bardoxolone methyl, called RTA-408 (Omaveloxone), is now under clinical investigation in phase II clinical trials for Friedreich’s ataxia, ocular inflammation, and pain after ocular surgery [50]. Recently, a preclinical study evaluated RTA-408 for diabetic wound recovery and pointed NRF2 upregulation as responsible for the observed improvement in regenerative capacity.