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 engineered to overexpress P-glycoprotein (P-gp) or naturally expressing P-gp, Genz-123346's chemosensitization effects are primarily attributed to its impact on P-gp function. Genz-123346, also known as Genz, promotes autophagy flux. Additionally, when cells are exposed to Genz-123346 and other glucosylceramide synthase (GCS) inhibitors at non-toxic levels, there is an enhancement in the efficacy of cytotoxic anticancer agents in eliminating tumor cells. Moreover, Genz-123346, along with select GCS inhibitors, acts as substrates for multi-drug resistance efflux pumps, including P-gp (ABCB1, gP-170), suggesting their role in overcoming drug resistance mechanisms.

In Zucker diabetic fatty rats, Genz-123346 significantly reduced glucose and A1C levels while enhancing glucose tolerance. This drug treatment also preserved pancreatic beta-cell function and maintained insulin secretion capacity. Additionally, in diet-induced obese mice, Genz-123346 normalized A1C levels and improved glucose tolerance. The drug's oral bioavailability was recorded at about 10% in mice and 30% in rats, with a plasma half-life of 30–60 minutes. Genz-123346 administration led to a dose-dependent decrease in renal GlcCer and GM3 levels, effectively inhibiting cystic disease through its impact on the Akt-mTOR signaling pathway, notably decreasing phosphorylation of Akt and ribosomal protein S6. In a study with WT mice treated with Genz-123346 (0.11% final concentration in regular chow) for two weeks, renal Gb3 levels were halved compared to WT mice on a standard chow diet.