P053

P053 is an inhibitor of ceramide synthase 1 (CerS1; IC50s = 0.54 and 0.46 µM for human and mouse CerS1, respectively). It is selective for CerS1 over CerS2, CerS4, CerS5, and CerS6 (IC50s = 28.6, 17.2, 7.2, and 11.4 µM, respectively). P053 decreases the production of C18 ceramide from dihydrosphingosine in cortical neuron cultures in a concentration-dependent manner. It also lowers levels of C18 ceramide, C18 galactosylceramide, and C18:0 and 18:1 sphingomyelin species in HEK293 cells, when used at concentrations ranging from 30 to 300 nM, without inducing cell death. P053 (5 mg/kg) decreases endogenous C18 and C18:2/18:0 ceramide levels and increases C22:0 , C24:0 , and C24:1 ceramide levels in mouse skeletal muscle. It increases fatty acid oxidation in mouse skeletal muscle and inhibits triglyceride synthesis and increases in white adipose mass in a model of high-fat diet-induced obesity but does not affect insulin resistance.