title: 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.
authors.affiliation: Reata Pharmaceuticals, Irving, TX 75063, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Chin
authors.forename: Chun-Yue Ivy
authors.initials: CY
authors.lastname: Lee
authors.forename: Jen-Chieh
authors.initials: JC
authors.lastname: Chuang
authors.forename: Ron
authors.initials: R
authors.lastname: Bumeister
authors.forename: W Christian
authors.initials: WC
authors.lastname: Wigley
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Sonis
authors.forename: Keith W
authors.initials: KW
authors.lastname: Ward
authors.forename: Colin
authors.initials: C
authors.lastname: Meyer
mesh_terms: D000818:Animals; D003404:Creatinine / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004041:Dietary Fats / Q000008:administration & dosage; D004435:Eating / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007668:Kidney / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy*; D009828:Oleanolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051381:Rats; D011924:Rats, Zucker
chemical_list: C518860:2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid ethyl amide; D004041:Dietary Fats; C547749:dh404 compound; D009828:Oleanolic Acid; D003404:Creatinine; C445068:bardoxolone methyl; D005947:Glucose
keywords: Type 2 diabetes; bardoxolone methyl