P053 is a potent, non-competitive, and selective ceramide synthase 1 (CerS1) inhibitor with an IC50 of 0.5 μM. It acts as an endogenous inhibitor of mitochondrial fatty acid oxidation in muscle and regulates 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 represents the inaugural isoform-specific ceramide synthase inhibitor exhibiting nanomolar efficacy. It selectively targets various human (h) and murine (m) CerS isoforms -- namely hCerS1, mCerS1, hCerS2, mCerS2, hCerS4, mCerS5, and hCerS6 -- displaying IC50 values 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].

Administered orally at a dosage of 5 mg/kg daily for a week to male C57BL6/J mice, P053 significantly reduces C18 ceramide levels in skeletal muscle (SkM) [1]. Additionally, when given to mice consuming a high-fat diet (HFD), P053 enhances fatty acid oxidation in SkM, prevents increases in muscle triglycerides and adiposity, but does not prevent HFD-induced insulin resistance [1]. This effect is specific to the 5 mg/kg dosage, as a lower dosage of 1 mg/kg per day does not yield the same reduction in C18 ceramide levels in SkM.