P053 is a potent, non-competitive and selective ceramide synthase 1 (CerS1) inhibitor with an IC50 of 0.5 μM. P053 is an endogenous inhibitor of mitochondrial fatty acid oxidation in muscle and regulator of whole-body adiposity[1].

CerS1 (mouse):0.46±0.08 μM , CerS2 (human):28.6±0.15 μM , CerS6 (human):11.4±0.17 μM , CerS4 (human):17.2±0.09 μM , CerS2 (mouse):18.5±0.12 μM , CerS5 (mouse):7.2±0.10 μM , CerS1 (human):0.54±0.06 μM

P053 is the first isoform-specific ceramide synthase inhibitor with nanomolar potency. P053 inhibits different human (h) or murine (m) CerS isoforms hCerS1, mCerS1, hCerS2, mCerS2, hCerS4, mCerS5, and hCerS6 with IC 50 s 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].

P053 (5 mg/kg; administered daily by oral gavage; 7 days, in male C57BL6/J mice ) lowers 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 while not protect against HFD-induced insulin resistance [1]. Animal Model: Male C57BL6/J mice [1] Dosage: 5 mg/kg Administration: Oral gavage; daily Result: Reduced C18 ceramide levels in SkM by 31%, whereas 1 mg/kg/day had no effect.