Glucosylceramide synthase-IN-3 (compound BZ1) is a highly potent, brain-penetrant, and orally active inhibitor of glucosylceramide synthase (GCS), exhibiting an IC50 value of 16 nM for human GCS. This compound, designated as Glucosylceramide synthase-IN-3, finds potential applications in Gaucher's disease research [1] [2].

Glucosylceramide Synthase-IN-2 (compound BZ1) effectively reduces glucosylceramide levels, with cellular IC50 values of 94 nM in humans and 160 nM in mice, as confirmed through a fibroblast assay [1]. Additionally, it exhibits a potent IC50 of 20 nM in primary neurons [1]. Compound BZ1 demonstrates a dose-dependent decrease in glycosphingolipids across both wild-type and D409V mouse cortical neurons at concentrations of 10, 30, 100, and 300 nM. Moreover, it significantly reduces the levels of detergent-insoluble pS129 α-syn [1], indicating its broad-spectrum efficacy in biological models.

Eight hours following administration of a single dose, Glucosylceramide synthase-IN-2 (compound BZ1; administered at 6, 20, or 100 mg/kg through oral gavage and formulated in 30% captisol) demonstrates a dose-dependent reduction in plasma GlcCer C:16:0 levels, achieving a decrease of approximately 75% compared to vehicle-treated animals. Additionally, this compound significantly lowers brain GlcCer levels to about 48% relative to vehicle-treated controls in male C57BL6 mice aged 8 weeks. Extended administration of Glucosylceramide synthase-IN-2 (6, 20, or 100 mg/kg/day over four days) results in even greater reductions in GlcCer levels. The compound also exhibits favorable pharmaceutical properties, including high permeability (pApp=26.54) and a lack of P-gp substrate activity.