Shanghai Nianxing Industrial Co., Ltd
China
Product Name: Genz-123346?
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Purity: 98.0%
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943344-58-9

943344-58-9 structure

943344-58-9 structure

Name: Genz-123346
Chemical Name: Genz-123346
CAS Number: 943344-58-9
Molecular Formula: C₅₂H₈₂N₄O₁₄
Molecular Weight: 987.226
Catalog: Research Areas Metabolic Disease
Create Date: 2018-01-13 09:08:56
Modify Date: 2024-01-10 10:23:25
Genz-123346 is an inhibitor of GL1 synthase that blocks the conversion of ceramide to GL1; inhibits GM1 with IC50 value of 14 nM.

Name	Genz-123346
Synonyms	(2R,3R)-2,3-Dihydroxysuccinic acid - N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-(1-pyrrolidinyl)-2-propanyl]nonanamide (1:2) Butanedioic acid, 2,3-dihydroxy-, (2R,3R)-, compd. with N-[(1R,2R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-hydroxy-1-(1-pyrrolidinylmethyl)ethyl]nonanamide (1:2)

Description	Genz-123346 is an inhibitor of GL1 synthase that blocks the conversion of ceramide to GL1; inhibits GM1 with IC50 value of 14 nM.
Related Catalog	Signaling Pathways >> Others >> Others Research Areas >> Metabolic Disease
Target	IC50: 14 nM (GM1)[1]
In Vitro	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 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[2]. Genz-123346(Genz) is an enhancer of autophagy flux[3].
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].
Animal Admin	Rats: Genz-123346 is dissolved in water. Zucker diabetic fatty rats treated with Genz-123346 (75 mg/kg) for 6 weeks are fasted overnight. The following morning, the fasted rats are anesthetized and injected with 5 units human insulin into the hepatic portal vein. Quadriceps muscle and liver are harvested 2 min after injection and immediately frozen in liquid nitrogen. Insulin receptor is immunoprecipitated. The immunoprecipitates are analyzed by immunoblotting[1]. Mice: C57BL/6 mice are fed on a high-fat (45% of kcal) diet for 8 weeks, obese mice with comparable body weight gain, glucose, and insulin levels are assigned to either the treated or control groups. The mice are then gavaged daily with Genz-123346 or water for 10 weeks[1].
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. [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. [3]. Shen W, et al. Inhibition of glucosylceramide synthase stimulates autophagy flux in neurons. J Neurochem. 2014 Jun;129(5):884-94 [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.

Molecular Formula	C₅₂H₈₂N₄O₁₄
Molecular Weight	987.226
Exact Mass	986.582764
Storage condition	2-8℃