Genz-123346 是一种口服有效的葡萄糖神经酰胺合酶

Genz-123346  

Genz-123346 是一种口服有效的葡萄糖神经酰胺合酶 (glucosylceramide synthase) 抑制剂。Genz-123346 阻断神经酰胺向葡萄糖神经酰胺 (GL1) 的转化，并抑制 GM1，IC₅₀ 值为 14 nM。

美国medchemexpress（MCE)浙江省一级代理:杭州昊鑫生物科技股份有限公司
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生物活性    
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].

IC50 & Target    
IC50: 14 nM (GM1)[1]

体外研究(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].

体内研究(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].

分子量    
987.23

Formula    
C52H82N4O14

CAS 号    
943344-58-9

运输条件    
Room temperature in continental US; may vary elsewhere.

储存方式    
Please store the product under the recommended conditions in the Certificate of Analysis.

参考文献

[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.  [Content Brief] [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.  [Content Brief] [3]. Shen W, et al. Inhibition of glucosylceramide synthase stimulates autophagy flux in neurons. J Neurochem. 2014 Jun;129(5):884-94  [Content Brief] [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.  [Content Brief] [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.  [Content Brief]

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