Genz-123346 blocks the conversion of ceramide to glucosylceramide (GL1) and inhibits GM1 with an IC50 value of 14 nM. Genz-123346 is a potent, orally available glucosylceramide synthase inhibitor.

GM1:14 nM

In cell lines selected to over-express P-gp or which endogenously express P-gp, chemosensitization by Genz-123346 is primarily due to the effects on P-gp function. Genz-123346(Genz) is an enhancer of autophagy flux.Exposure of cells to Genz-123346 and to other GCS inhibitors at nontoxic concentrations can enhance the killing of tumor cells by cytotoxic anti-cancer agents.?Genz-123346 and a few other GCS inhibitors are substrates for multi-drug resistance efflux pumps such as P-gp (ABCB1, gP-170).

In the Zucker diabetic fatty rat, Genz-123346 loared glucose and A1C levels and improved glucose tolerance.?Drug treatment also prevented the loss of pancreatic beta-cell function and preserved the ability of the animals to secrete insulin.?In the diet-induced obese mouse, treatment with Genz-123346 normalized A1C levels and improved glucose tolerance.?The oral bioavailability of the drug is shown to be about 10% and 30% in mice and rats, respectively, with a half-life in plasma of 30–60 min. Genz-123346 treatment results in a dose-dependent reduction of renal GlcCer and GM3 levels that translates into effective inhibition of cystic disease.?A direct effect of Genz-123346 on the Akt-mTOR signaling pathway is observed, with reduced phosphorylation of Akt and ribosomal protein S6.?A group of WT mice received Genz-123346 (0.11% final concentration in regular chow);?after 2 weeks of feeding, renal Gb3 was reduced by approximately 50%, in comparison with WT mice fed with chow diet only.