CKD‐501, a novel selective PPARγ agonist, shows no carcinogenic potential in ICR mice following oral administration for 104 weeks

Abstract

CKD-501 is a peroxisome proliferator-activated receptor gamma (PPARγ) agonist that is effective for the treatment of diabetes. However, its carcinogenic potential remains controversial. The current carcinogenicity study was conducted over a period of 104 weeks in ICR mice. Three groups, each consisting of 60 male and 60 female mice, received oral CKD-501 dosages of 0.2, 1.0 or 6.0 mg kg(-1) day(-1). The mortality rates of the male control, 0.2, 1.0 and 6.0 mg kg(-1) day(-1) treated groups were 60%, 68%, 58% and 67%, respectively and 57%, 68% and 67% in the female control, 0.2 and 1.0 mg kg(-1) day(-1) treated groups. It was 67% in the female 6.0 mg kg(-1) day(-1) treated group, which was terminated at week 98 due to its increased mortality rate. No significant treatment-related effects were observed on the survival rates, with the exception of females in the 6.0 mg kg(-1) day(-1) group. Body weights increased in females receiving 1.0 and 6.0 mg kg(-1) day(-1) due to the class effects of the PPARγ agonist. Differences were not found in hematology parameters between the CKD-501-treated groups and their corresponding controls, but the histopathological evidence did not reveal any findings attributed to CKD-501. Treated animals exhibited non-neoplastic findings (adipocyte proliferation, bone marrow hypoplasia cardiomyopathy), but all of these were expected changes for this class of compound. There were no treatment-related neoplastic changes in this study. The results of this study therefore demonstrate a lack of carcinogenicity following oral administration of CKD-501 to ICR mice for 104 weeks.

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

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“…PPARγ Pioglitazone III (130) Increased limb fat deposition, but did not improve lipid profile [153] Rosigltazone NA (96) No improvement in lipoatrophy [155] NA (39) Increased subcutaneous and visceral abdominal fat Improved insulin sensitivity and adiponectin Did not affect CRP and flow-mediated vasodilation [156] II (71) Did not improve carotid intima media thickness, inflammatory markers and endothelial activation markers [157] Pan-PPAR Tetradecylthioacetic acid NA (10) Tetradecylthioacetic acid with diet intervention reduced total cholesterol, LDL cholesterol, triglycerides, LDL/HDL cholesterol ratio, and TNF-α [ 6. Metabolic Syndrome, Obesity, and Hypertension…”

Structures of PPARγ complexed with lobeglitazone and pioglitazone reveal key determinants for the recognition of antidiabetic drugs

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The Antidiabetic Drug Lobeglitazone Protects Mice From Lipogenesis-Induced Liver Injury via Mechanistic Target of Rapamycin Complex 1 Inhibition

“…Lobeglitazone has similar efficacy in lipid metabolism to pioglitazone with even smaller dose in clinical studies ( 42 , 43 ). In addition, lobeglitazone showed markedly reduction of adverse effects, such as cardiovascular disease and bladder cancer ( 44 , 45 ). TZDs including lobeglitazone primarily act as PPARγ agonists in adipose tissue.…”