Bardoxolone methyl analogs RTA 405 and dh404 are well tolerated and exhibit efficacy in rodent models of Type 2 diabetes and obesity

Abstract

Bardoxolone methyl and related triterpenoids are well tolerated and efficacious in numerous animal models potentially relevant to patients with Type 2 diabetes and chronic kidney disease. These agents enhance glucose control and regulate lipid accumulation in rodent models of diabetes and obesity, and improve renal function, reduce inflammation, and prevent structural injury in models of renal disease. However, a recent study in Zucker diabetic fatty (ZDF) rats noted poor tolerability with the bardoxolone methyl analog RTA 405 within 1 mo after treatment initiation, although this study was confounded in part by the use of an impure RTA 405 batch. To investigate these discordant observations, the present studies were conducted to further characterize triterpenoids in rodent models of diabetes and obesity. A follow-up study was conducted in ZDF rats with two related triterpenoids (RTA 405 and dh404) for 1.5 mo. Consistent with previous rodent experience, and in contrast to the more recent ZDF report, ZDF rats administered RTA 405 or dh404 exhibited no adverse clinical signs, had laboratory values similar to controls, and exhibited no evidence of adverse liver or kidney histopathology. Additionally, RTA 405 was well tolerated in streptozotocin-induced Type 1 diabetic rats and high-fat-diet-induced obese mice. The present results are consistent with the overall published body of data obtained with triterpenoids and provide further evidence that these molecules are well tolerated without adverse effects on hepatobiliary or renal function in rodent models of diabetes and obesity.

Derivative of Bardoxolone Methyl, dh404, in an Inverse Dose-Dependent Manner Lessens Diabetes-Associated Atherosclerosis and Improves Diabetic Kidney Disease

“…Differences in outcome between our study and that of Zoja et al (23) may reflect subtle disparity in drug dosage as well as differences in drug bioavailability between species. Our findings are, however, more in agreement with the study by Chin et al (24), in which it was shown that the BM analogs RTA 405 and dh404 were well tolerated in various rodent models of type 2 diabetes. Our study is also in agreement with the notion that activators of Nrf2 protect against diabetic nephropathy (9).…”

“…Livers were stained with hematoxylin and eosin and scored blinded on a scale of 0-5 to determine hepatocellular cytoplasmic rarification and periportal inflammation (24). Five to eight livers were examined per group.…”

“…Potential problems with toxicity and a worsening of diabetic nephropathy were also raised in a preclinical study examining the effects of BM analogs RTA 405 and dh404 on renal outcomes in diabetic Zucker fat rats (23). The issue of toxicity was subsequently addressed in a follow-up study (24) that showed that RTA 405 and dh404 are well tolerated and did not confirm the previous report of hepatic and renal toxicity.…”

Dysregulation of Nrf2 Signaling in Diabetes: An Opportunity for a Multitarget Approach

“…However, it was believed that impure compounds were responsible for the adverse effects in those studies [51]. Follow up studies demonstrated that using structural analogs lacking the impurities and at appropriate doses were unable to reproduce the adverse effects and that Dh404 is in fact well tolerated and exhibits efficacy in rodent models of T2DM [52]. It is believed these negative side effects were due to impure compounds and that Dh404 is both efficacious and well tolerated in several animal models and in humans.…”

Identification of potential mediators of oxidative damage and targets for novel treatments for chronic kidney disease

“…Wu et al (2011) (Zoja et al, 2013). Despite this, rodent models examining kidney parameters continually showed efficacy of bardoxolone methyl and triterpenoid analogs (Reisman et al, 2012;Chin et al, 2013;Ding et al, 2013), giving reason to continue research into targeting the Nrf2 pathway. As previously mentioned, the Keap1-Nrf2 pathway is a highly conserved, ubiquitous response not only to stress, but also responsible for constitutive expression of genes regulated by ARE during basal conditions.…”