| Identification | Back Directory | [Name]
Genz-123346 | [CAS]
943344-58-9 | [Synonyms]
Genz
Genz-123346
(Genz123346)
N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]nonanamide | [Molecular Formula]
C52H82N4O14 | [MOL File]
943344-58-9.mol | [Molecular Weight]
987.226 |
| Hazard Information | Back Directory | [Uses]
Genz-123346 is a potent, orally available glucosylceramide synthase inhibitor. Genz-123346 blocks the conversion of ceramide to glucosylceramide (GL1) and inhibits GM1 with an IC50 value of 14 nM[1]. | [in vivo]
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[1].
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[4].
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[5]. | [storage]
Store at -20°C | [References]
[1] Zhao H, et al. Inhibiting glycosphingolipid synthesis improves glycemic control and insulin sensitivity in animal models of type 2 diabetes. Diabetes. 2007 May;56(5):1210-8. DOI:10.2337/db06-0719
[2] Chai L, et al. The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function. Int J Oncol. 2011 Mar;38(3):701-11. DOI:10.3892/ijo.2010.888
[3] Shen W, et al. Inhibition of glucosylceramide synthase stimulates autophagy flux in neurons. J Neurochem. 2014 Jun;129(5):884-94 DOI:10.1111/jnc.12672
[4] Natoli TA, et al. Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models. Nat Med. 2010 Jul;16(7):788-92. DOI:10.1038/nm.2171
[5] Morace I, et al. Renal globotriaosylceramide facilitates tubular albumin absorption and its inhibitionprotects against acute kidney injury. Kidney Int. 2019 Aug;96(2):327-341. DOI:10.1016/j.kint.2019.02.010 |
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Musechem
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www.musechem.com |
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BOC Sciences
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www.bocsci.com |
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