Elafibranor(GFT505)

Description

Elafibranor is an agonist of the peroxisome proliferator-activated receptors (PPAR) α and δ. It increases HDL secretion and expression of the lipid-related genes ABCA1, PLIN2, and ABHD5 in Caco-2/TC7 cells in a PPARα-dependent manner. Elafibranor (10 mg/kg) decreases levels of plasma triglycerides and total cholesterol while increasing plasma HDL and expression of Acox1, a PPARα target gene, in the liver of ApoE2-KI wild-type, but not PPARα knockout, mice fed a Western diet. However, PPARα knockout mice exhibit a decrease in plasma total and non-HDL cholesterol levels, indicating PPARδ has a role in these functions. Elafibranor (30 mg/kg) reduces diet-induced macro- and micro-steatosis in a PPARα-deficient mouse model of non-alcoholic steatohepatitis. It also reduces cholesterol and triglyceride accumulation as well as macrovesicular steatosis in the liver of insulin-resistant db/db mice fed the methionine-choline deficient (MCD) diet. Formulations containing elafibranor are under clinical investigation for the treatment of non-alcoholic steatohepatitis.

Uses

GFT-505 is a?dual?PPARα/δ agonist. Studies have shown that GFT-505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. It may also be a potential new drug candidate for treating lipid and glucose disorders.

Biological Functions

Elafibranor (GFT505) is an agonist of peroxisome proliferator-activated receptor (PPAR) alpha and delta. EC50 values were 45 and 175 nM, respectively. GFT505 is being developed as a dual PPAR-α/PPAR-δ receptor agonist for the treatment of type 2 diabetes and nonalcoholic fatty liver disease. GFT1007 and GFT505 have an active metabolite, both with potent stimulant activity PPAR-α and to a lesser extent PPAR-δ.

Biological Activity

Elafibranor (GFT505) is an agonist of PPAR-alpha and PPAR-delta, improves insulin sensitivity, benefits glucose homeostasis, lipid metabolism and reduces inflammation.

in vivo

IC 50

PPAR-α: 45 nM (EC₅₀); PPAR-δ: 175 nM (EC₅₀)

References

1) Cariou?et al.?(2011)?Effects of the New Dual PPARα/δ Agonist GFT505 on Lipid and Glucose Homeostasis in Abdominally Obese Patients With Combined Dyslipidemia or Impaired Glucose Metabolism; Diabetes Care?34?2008 2) Cariou?et al.?(2013)?Dual peroxisome proliferator receptor α/δ agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects; Diabetes Care?36?2923 3) Hanf?et al.?(2014)?The dual peroxisome proliferator-activated alpha/delta agonist GFT505 exerts anti-diabetic effects in db/db mice without peroxisome proliferator-activated receptor gamma-associated adverse cardiac effects.; Diab. Vasc. Dis. Res.?11?440 4) Staels?et al.?(2013)?Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha-delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis; Hepatology?58?1941 5) Ratziu?et al.?(2016)?Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening.; Gastroenterology.?39?2951 6) Boeckmans?et al. (2019)?Elafibranor restricts lipogenic and inflammatory responses in a human skin stem cell-derived model of NASH.; Pharmacol. Res.?114?377