P053

P053 is a potent, non-competitive and selective ceramide synthase 1 (CerS1) inhibitor wirh an IC₅₀ of 0.5?μM. P053 acts as an endogenous inhibitor of mitochondrial fatty acid oxidation in muscle. Whole-body adiposity regulator^[1]. IC50 & Target:IC50: 0.54±0.06 μM (hCerS1), 0.46±0.08 μM (mCerS1), 28.6±0.15 μM (hCerS2), 18.5±0.12 μM (mCerS2), 17.2±0.09 μM (hCerS4), 7.2±0.10 μM (mCerS5), 11.4±0.17 μM (hCerS6)^[1] In Vitro: P053 is the first isoform-specific ceramide synthase inhibitor. P053 inhibits CerS1 with nanomolar potency. P053 inhibits different human (h) or murine (m) CerS isoforms hCerS1, mCerS1, hCerS2, mCerS2, hCerS4, mCerS5, and hCerS6 with IC₅₀s of 0.54±0.06, 0.46±0.08, 28.6±0.15, 18.5±0.12, 17.2±0.09, 7.2±0.10, and 11.4±0.17 μM, respectively^[1]. In Vivo: P053 (5?mg/kg; administered daily by oral gavage; 7 days, in male C57BL6/J mice ) reduces C18 ceramide levels in skeletal muscle (SkM) ^[1].
Daily P053 administration to mice fed a high-fat diet (HFD) increases fatty acid oxidation in skeletal muscle and impedes increases in muscle triglycerides and adiposity, but does not protect against HFD-induced insulin resistance^[1].