MSDC-0602

MSDC-0602 is a PPARγ-sparing thiazolidinedione derivative.¹ It binds only weakly to PPARγ (IC₅₀ = 18.25 µM) and induces minimal activation of a Gal4-PPARγ reporter construct when used at a concentration of 50 µM. MSDC-0602 binds to mitochondrial membranes and decreases the pyruvate-induced oxygen consumption rate in control mitochondria but not in liver-specific mitochondrial pyruvate carrier 2 knockout (LS-Mpc2^-/-) mitochondria.² It reduces body weight gain and adiposity, as well as increases intrascapular brown adipose tissue (BAT) mass in a mouse model of non-alcoholic steatohepatitis (NASH) induced by a high-trans-fat, -fructose, and -cholesterol diet when administered in the diet for 12 weeks, starting four weeks after the beginning of the diet.³ It also reverses hepatic fibrosis and stellate cell fibrinogenesis when administered for three weeks, starting 16 weeks after the beginning of the diet. MSDC-0602 decreases plasma glucose, triglyceride, and cholesterol levels in ob/ob mice and increases insulin sensitivity in the striatal muscle, adipose tissue, and liver of diet-induced obese mice.¹

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1. Chen, Z., Vigueira, P.A., Chambers, K.T., et al. Insulin resistance and metabolic derangements in obese mice are ameliorated by a novel peroxisome proliferator-activated receptor γ-sparing thiazolidinedione. The Journal of Biological Chemisty 287(28), 23537-23548 (2012).

2. McCommis, K.S., Chen, Z., Fu, X., et al. Loss of mitochondrial pyruvate carrier 2 in the liver leads to defects in gluconeogenesis and compensation via pyruvate-alanine cycling. Cell Metab. 22(4), 682-694 (2015).

3. McCommis, K.S., Hodges, W.T., Brunt, E.M., et al. Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis. Hepatology 65(5), 1543-1556 (2017).