ChemicalBook Product Catalog Biochemical Engineering Biochemical Reagents Agonist Inhibitors 4-IsoxazolecarboxaMide, 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N,5-diMethyl-

4-IsoxazolecarboxaMide, 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N,5-diMethyl-

Product Name4-IsoxazolecarboxaMide, 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N,5-diMethyl-
CAS1197300-24-5
MFC18H14Cl2N2O2
MW361.22
EINECS200-256-5
MOL File1197300-24-5.mol

Chemical Properties

Boiling point	541.8±50.0 °C(Predicted)
Density	1.346±0.06 g/cm3(Predicted)
storage temp.	2-8°C
solubility	DMF: 50 mg/ml; DMSO: 50 mg/ml; DMSO:PBS (pH 7.2) (1:4): 0.2 mg/ml; Ethanol: 30 mg/ml
form	A crystalline solid
pka	-0.52±0.50(Predicted)
color	White to off-white

Usage And Synthesis

Description

TGR5 receptor agonist is an agonist of the bile acid G protein-coupled receptor TGR5 (EC₅₀s = 31.6-158.5 nM in cell-based assays). It stimulates cAMP formation in HEK293 cells expressing TGR5 (EC₅₀ = 2.3 pM). TGR5 receptor agonist (1 mg/kg) increases glucagon-like peptide 1 (GLP-1) secretion and decreases glucose levels in the hepatic portal vein in dogs when administered in combination with glucose. It also inhibits the cytochrome P450 (CYP) isozymes CYP2C19 and CYP3A4 (IC₅₀s = 316.2 and 1,259 nM, respectively).

Uses

TGR5 Receptor Agonist (CCDC), a potent Takeda G protein-coupled receptor 5 (TGR5; GPCR19) agonist, shows improved potency in the U2-OS cells and melanophore cells with pEC50s of 6.8 and 7.5, respectively. TGR5 Receptor Agonist can induce peripheral and central hypersensitivity to bladder distension in mice, and increase intracellular Ca2+ concentration. TGR5 Receptor Agonist can also reduces food intake and improves insulin responsiveness, in diet-induced obese mice. TGR5 Receptor Agonist can be used to research diabetes, bladder hypersensitivity and anti-obesity[1][2][3][4].

in vivo

TGR5 Receptor Agonist (CCDC) activates directly a sub-population of bladder-innervating dorsal root ganglia (DRG) neurons and a small percentage of non-neuronal cells in Trpv1^-/- mice^[2].
TGR5 Receptor Agonist (CCDC) (2or 5 μg; ICV) reduces food intake and body weight in diet-induced obese mice^[3].

Animal Model:	Female C57BL/6J mice [12-18 weeks; TRPV1 knockout (trpv1^-/-), TRPA1 knockout (trpa1^-/-), or TGR5 knockout (Gpbar1^-/-)]^[2]
Dosage:	100 μM, 100 μL
Administration:	Infused gently, to fill but not fully distend the bladder, and allowed to incubate for 5 min
Result:	Activated directly a sub-population of bladder-innervating dorsal root ganglia (DRG) neurons in Trpv1^-/- mice, also activated a small percentage of non-neuronal cells. Increased intracellular Ca²⁺ in bladder-innervating DRG neurons. Increased intracellular Ca²⁺ in a small proportion of non-neuronal cells.

Animal Model:	Male C57BL/6J mice (obese induced by high-fat diet)^[3]
Dosage:	2or 5 μg at a volume of 0.2 μL per brain side and a rate of 0.6 μL/min
Administration:	ICV (acute intra-hypothalamic experiment)
Result:	Significantly reduced food intake over time, with a robust reduction in 24 h food intake and body weight gain.

Animal Model:	Male C57BL/6J mice (obese induced by high-fat diet; implanted with micro-osmotic pumps that were filled with CCDC)^[3]
Dosage:	5 μg/day; 91.9 μL, pumping rate of 0.09 μL/h
Administration:	ICV; for 4 weeks (chronic experiment)
Result:	Reduced food intake and improved insulin responsiveness. Increased energy expenditure during the dark phase. Increased mRNA expression of β1, 2, and 3 adrenoreceptors (Adrb1, Adrb2, and Adrb3) in the epidydimal white adipose tissue, and increased Dio2 (the gene expressing the enzyme D2) in brown adipose tissue.

References

[1] Evans KA, et al. Discovery of 3-aryl-4-isoxazolecarboxamides as TGR5 receptor agonists. J Med Chem. 2009 Dec 24;52(24):7962-5. DOI:10.1021/jm901434t
[2] Caldwell A, Grundy L, Harrington AM, Garcia-Caraballo S, Castro J, Bunnett NW, Brierley SM. TGR5 agonists induce peripheral and central hypersensitivity to bladder distension. Sci Rep. 2022 Jun 15;12(1):9920. DOI:10.1038/s41598-022-14195-w
[3] Castellanos-Jankiewicz A, et al. Hypothalamic bile acid-TGR5 signaling protects from obesity. Cell Metab. 2021 Jul 6;33(7):1483-1492.e10. DOI:10.1016/j.cmet.2021.04.009

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