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GSK 2330672

Product NameGSK 2330672
CAS1345982-69-5
MFC28H38N2O7S
MW546.68
EINECS604-604-1
MOL File1345982-69-5.mol

Chemical Properties

Boiling point	730.8±60.0 °C(Predicted)
Density	1.218±0.06 g/cm3(Predicted)
storage temp.	Store at -20°C
solubility	DMF: 5 mg/ml; DMSO: 2 mg/ml; PBS (pH 7.2): 0.2 mg/ml
form	A crystalline solid
pka	3.27±0.10(Predicted)
color	White to off-white
InChIKey	CZGVOBIGEBDYTP-VSGBNLITSA-N
SMILES	C(O)(=O)CC(NCC1C=C2S(=O)(=O)C[C@](CCCC)(CC)N[C@H](C3=CC=CC=C3)C2=CC=1OC)CC(O)=O

Usage And Synthesis

Description

GSK2330672 is an inhibitor of the apical sodium-dependent bile acid transporter (ASBT; IC₅₀s = 42, 2.1, and 1.9 nM for human, mouse, and rat ASBT, respectively). In vivo, GSK2330672 (0.05 mg/kg) stimulates fecal bile acid secretion, reduces hemoglobin A1c (HbA1c) and plasma glucose levels, and increases total GLP-1 and plasma insulin in Zucker diabetic fatty (ZDF) rats.

Uses

Linerixibat (GSK2330672) is a highly potent, nonabsorbable and orally active apical sodium-dependent bile acid transporter (ASBT) inhibitor with an IC50 of 42 nM human ASBT. Linerixibat can be used as lipid-lowering agent. Linerixibat has the potential for type 2 diabetes and Primary Biliary Cholangitis treatment[1][2][3].

in vivo

Linerixibat (GSK2330672; 0.05-10 mg/kg; oral gavage; twice daily; for 14 days; male ZDF rat) treatment lowers glucose in an animal model of type 2 diabetes^[1].

Animal Model:	Male Zucker Diabetic Fatty (ZDF) rat^[1]
Dosage:	0.05 mg/kg, 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg
Administration:	Oral gavage; twice daily; for 14 days
Result:	Led to a 1.30-1.64% reduction in hemoglobin A1c (HbA1c), a greater than 50% reduction in nonfasted plasma glucose to below 200 mg/dL, and statistically significant higher plasma insulin.

References

[1] Wu Y, et al. Discovery of a highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 diabetes. J Med Chem. 2013 Jun 27;56(12):5094-114. DOI:10.1021/jm400459m
[2] Wang Y, et al. HNF4α Regulates CSAD to Couple Hepatic Taurine Production to Bile Acid Synthesis in Mice. Gene Expr. 2018 Aug 22;18(3):187-196. DOI:10.3727/105221618X15277685544442
[3] Linerixibat (GSK2330672) granted Orphan Status. September 24, 2019.

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