Details
Stereochemistry | ABSOLUTE |
Molecular Formula | 2C24H38N2O4.C4H6O6 |
Molecular Weight | 987.2259 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 6 / 6 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
O[C@H]([C@@H](O)C(O)=O)C(O)=O.CCCCCCCCC(=O)N[C@H](CN1CCCC1)[C@H](O)C2=CC=C3OCCOC3=C2.CCCCCCCCC(=O)N[C@H](CN4CCCC4)[C@H](O)C5=CC=C6OCCOC6=C5
InChI
InChIKey=ZRGZTIAIHNUMCZ-DQKXIDSGSA-N
InChI=1S/2C24H38N2O4.C4H6O6/c2*1-2-3-4-5-6-7-10-23(27)25-20(18-26-13-8-9-14-26)24(28)19-11-12-21-22(17-19)30-16-15-29-21;5-1(3(7)8)2(6)4(9)10/h2*11-12,17,20,24,28H,2-10,13-16,18H2,1H3,(H,25,27);1-2,5-6H,(H,7,8)(H,9,10)/t2*20-,24-;1-,2-/m111/s1
Molecular Formula | C4H6O6 |
Molecular Weight | 150.0868 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 2 / 2 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
Molecular Formula | C24H38N2O4 |
Molecular Weight | 418.5695 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 2 / 2 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
Genz-123346 is a potent and selective glucosylceramide synthase (GCS) inhibitor that blocks the conversion of ceramide to GL1. It has been studied as a potential treatment of diabetes mellitus, polycystic kidney disease and fatty liver disease. Genz-123346 improved glucose tolerance and increased insulin sensitivity in two animal models of type 2 diabetes. In Zucker diabetic fatty rats, treatment with Genz-123346 significantly lowered blood glucose levels and partially prevented the normal deterioration of pancreatic β-cell function over time and preserved the ability of the islets to secrete insulin. In the high-fat–fed diet-induced obese mice, Genz-123346 essentially normalized A1C levels to that of the lean animals. Inhibiting GSL synthesis ameliorates the liver pathology associated with obesity and diabetes in mice model. Blockade of kidney glucosylceramide GlcCer accumulation with the GCS inhibitor Genz-123346 effectively inhibits cystogenesis in mouse models orthologous to human autosomal dominant polycystic kidney disease (PKD) (Pkd1 conditional knockout mice) and nephronophthisis (jck and pcy mice). Molecular analysis in vitro and in vivo indicated that inhibition of GCS by Genz-123346 inhibited the AKT-mTOR signaling pathway. It induced autophagy via the AKT-mTOR signaling pathway in HEK293T cells, increased autophagy flux and reduced mutant α-syn levels in mouse primary neurons potentially via indendent mechanisms. 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. This chemosensitizing 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. Genz-123346 has little effect on 1-O-acylceramide synthase activity at concentrations that effectively inhibit GL1 synthase activity and therefore do not significantly elevate cell ceramide levels in vitro. Unlike N-butyldeoxynojirimycin (NB-DNJ), another inhibitor of GCS Genz-123346 does not inhibit α-glucosidase or glucocerebrosidase.
CNS Activity
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24494600
Curator's Comment: Genz, cannot penetrate the blood brain barrier
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: Q16739 Gene ID: 7357.0 Gene Symbol: UGCG Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/17470562 |
14.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/17470562
To evaluate the effects of inhibiting glycosphingolipid synthesis on glucose homeostasis, Genz-123346 was administered to Zucker diabetic fatty rats by daily gavage (75 mg/kg/day) for 6 weeks.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24494600
Western blot analysis showed that treating the primary neurons with 5 uM Genz-123346 for 48 h significantly reduces the levels of A53T mutant α-syn (hSyn-A53T) in primary cortical neurons from A53T transgenic mice (n = 9 per group).
Substance Class |
Chemical
Created
by
admin
on
Edited
Sat Dec 16 08:31:17 GMT 2023
by
admin
on
Sat Dec 16 08:31:17 GMT 2023
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Record UNII |
GQH5N7U72P
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Record Status |
Validated (UNII)
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Record Version |
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