Genz-123346
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MedKoo CAT#: 406141

CAS#: 491833-30-8

Description: Genz-123346 is a potent and selective glucosylceramide synthase inhibitor with potential anticancer activity. Exposure of cells to Genz-123346 and to other GCS inhibitors at non-toxic 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 was primarily due to the effects on P-gp function.


Chemical Structure

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Genz-123346
CAS# 491833-30-8

Theoretical Analysis

MedKoo Cat#: 406141
Name: Genz-123346
CAS#: 491833-30-8
Chemical Formula: C24H38N2O4
Exact Mass: 418.28316
Molecular Weight: 418.57
Elemental Analysis: C, 68.87; H, 9.15; N, 6.69; O, 15.29

Price and Availability

Size Price Availability Quantity
25.0mg USD 150.0 Same day
50.0mg USD 250.0 Same day
100.0mg USD 450.0 Same day
200.0mg USD 750.0 Same day
500.0mg USD 1450.0 Same day
1.0g USD 2250.0 Same day
2.0g USD 3950.0 Same day
5.0g USD 5650.0 2 weeks
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Synonym: Genz123346; Genz-123346; Genz 123346

IUPAC/Chemical Name: N-[(1R,2R)-1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl]nonanamide

InChi Key: JMNXWOFCUJJYEO-HYBUGGRVSA-N

InChi Code: InChI=1S/C24H38N2O4/c1-2-3-4-5-6-7-10-23(27)25-20(18-26-13-8-9-14-26)24(28)19-11-12-21-22(17-19)30-16-15-29-21/h11-12,17,20,24,28H,2-10,13-16,18H2,1H3,(H,25,27)/t20-,24-/m1/s1

SMILES Code: CCCCCCCCC(N[C@H](CN1CCCC1)[C@@H](C2=CC=C3OCCOC3=C2)O)=O

Appearance: White to off-white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >5 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Genz-123346 is a potent, orally available glucosylceramide synthase inhibitor and inhibits GM1 with an IC50 value of 14 nM.
In vitro activity: Exposure of cells to Genz-123346 at non-toxic concentrations can enhance the killing of tumor cells by cytotoxic anti-cancer agents. This activity was unrelated to lowering intracellular glycosphingolipid levels. Genz-123346 is a substrate 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 was primarily due to the effects on P-gp function. Reference: Int J Oncol. 2011 Mar;38(3):701-11. https://www.spandidos-publications.com/ijo/38/3/701
In vivo activity: In the Zucker diabetic fatty rat, the glucosylceramide synthase inhibitor (1R,2R)-nonanoic acid[2-(2',3'-dihydro-benzo [1, 4] dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]- amide-l-tartaric acid salt (Genz-123346) lowered glucose and A1C levels and improved glucose tolerance. Drug treatment also prevented the loss of pancreatic beta-cell function normally observed in the Zucker diabetic fatty rat 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. Analysis of the phosphorylation state of the insulin receptor and downstream effectors showed increased insulin signaling in the muscles of the treated Zucker diabetic fatty rats and diet-induced obese mice. Reference: Diabetes. 2007 May;56(5):1210-8. https://diabetes.diabetesjournals.org/lookup/pmidlookup?view=long&pmid=17470562

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 84.0 200.68
Ethanol 84.0 200.68

Preparing Stock Solutions

The following data is based on the product molecular weight 418.57 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
In vitro protocol: 1. Chai L, McLaren RP, Byrne A, Chuang WL, Huang Y, Dufault MR, Pacheco J, Madhiwalla S, Zhang X, Zhang M, Teicher BA, Carter K, Cheng SH, Leonard JP, Xiang Y, Vasconcelles M, Goldberg MA, Copeland DP, Klinger KW, Lillie J, Madden SL, Jiang YA. 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. Epub 2010 Dec 24. PMID: 21186402.
In vivo protocol: 1. Zhao H, Przybylska M, Wu IH, Zhang J, Siegel C, Komarnitsky S, Yew NS, Cheng SH. 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. PMID: 17470562. 2. Natoli TA, Smith LA, Rogers KA, Wang B, Komarnitsky S, Budman Y, Belenky A, Bukanov NO, Dackowski WR, Husson H, Russo RJ, Shayman JA, Ledbetter SR, Leonard JP, Ibraghimov-Beskrovnaya O. 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. Epub 2010 Jun 20. PMID: 20562878; PMCID: PMC3660226.

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1: Aerts JM, Boot RG, van Eijk M, Groener J, Bijl N, Lombardo E, Bietrix FM, Dekker N, Groen AK, Ottenhoff R, van Roomen C, Aten J, Serlie M, Langeveld M, Wennekes T, Overkleeft HS. Glycosphingolipids and insulin resistance. Adv Exp Med Biol. 2011;721:99-119. doi: 10.1007/978-1-4614-0650-1_7. Review. PubMed PMID: 21910085.

2: Silberstein C, Lucero MS, Zotta E, Copeland DP, Lingyun L, Repetto HA, Ibarra C. A glucosylceramide synthase inhibitor protects rats against the cytotoxic effects of shiga toxin 2. Pediatr Res. 2011 May;69(5 Pt 1):390-4. doi: 10.1203/PDR.0b013e318211dd57. PubMed PMID: 21270676.

3: Chai L, McLaren RP, Byrne A, Chuang WL, Huang Y, Dufault MR, Pacheco J, Madhiwalla S, Zhang X, Zhang M, Teicher BA, Carter K, Cheng SH, Leonard JP, Xiang Y, Vasconcelles M, Goldberg MA, Copeland DP, Klinger KW, Lillie J, Madden SL, Jiang YA. 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. Epub 2010 Dec 24. PubMed PMID: 21186402.

4: Schrier RW, Levi M. Lipids and renal cystic disease. Nephrol Dial Transplant. 2010 Nov;25(11):3490-2. doi: 10.1093/ndt/gfq545. Epub 2010 Sep 2. PubMed PMID: 20813766.

5: Takiar V, Caplan MJ. Telling kidneys to cease and decyst. Nat Med. 2010 Jul;16(7):751-2. doi: 10.1038/nm0710-751. PubMed PMID: 20613749.

6: Natoli TA, Smith LA, Rogers KA, Wang B, Komarnitsky S, Budman Y, Belenky A, Bukanov NO, Dackowski WR, Husson H, Russo RJ, Shayman JA, Ledbetter SR, Leonard JP, Ibraghimov-Beskrovnaya O. 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. Epub 2010 Jun 20. PubMed PMID: 20562878.

7: Karman J, Tedstone JL, Gumlaw NK, Zhu Y, Yew N, Siegel C, Guo S, Siwkowski A, Ruzek M, Jiang C, Cheng SH. Reducing glycosphingolipid biosynthesis in airway cells partially ameliorates disease manifestations in a mouse model of asthma. Int Immunol. 2010 Jul;22(7):593-603. doi: 10.1093/intimm/dxq044. Epub 2010 May 24. PubMed PMID: 20497953.

8: Zhao H, Przybylska M, Wu IH, Zhang J, Maniatis P, Pacheco J, Piepenhagen P, Copeland D, Arbeeny C, Shayman JA, Aerts JM, Jiang C, Cheng SH, Yew NS. Inhibiting glycosphingolipid synthesis ameliorates hepatic steatosis in obese mice. Hepatology. 2009 Jul;50(1):85-93. doi: 10.1002/hep.22970. PubMed PMID: 19444873.

9: Zhao H, Przybylska M, Wu IH, Zhang J, Siegel C, Komarnitsky S, Yew NS, Cheng SH. Inhibiting glycosphingolipid synthesis improves glycemic control and insulin sensitivity in animal models of type 2 diabetes. Diabetes. 2007 May;56(5):1210-8. PubMed PMID: 17470562.



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