Obeticholic Acid

Bezeichnung:Obeticholic Acid

CAS-Nr459789-99-2

Englisch Name:Obeticholic Acid

CBNumberCB92484652

SummenformelC26H44O4

Molgewicht420.63

MOL-Datei459789-99-2.mol

Obeticholic Acid physikalisch-chemischer Eigenschaften

Schmelzpunkt	108-110 °C
Siedepunkt	562.9±25.0 °C(Predicted)
Dichte	1.091
storage temp.	-20°C
Löslichkeit	Soluble in DMSO (up to 35 mg/ml) or in Ethanol (up to 25 mg/ml)
Aggregatzustand	White solid.
pka	4.76±0.10(Predicted)
Farbe	White
Stabilität	Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 2 months.

Sicherheit

HS Code

2918199890

Gefahreninformationscode (GHS)

Obeticholic Acid Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
Obeticholic acid is a potent and selective farnesoid X receptor agonist that promotes the flow of bile in the liver. The drug was approved by the USFDA for the treatment of the rare chronic liver disease primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with inadequate response to UDCA or as a single agent therapy in adults unable to tolerate UDCA. Obeticholic acid was discovered at the Università de Perugia and developed by Intercept Pharmaceuticals. Obeticholic acid has also been granted orphan drug designation for the treatment of primary sclerosing cholangitis and primary biliary cirrhosis and has received breakthrough therapy designation for the treatment of patients with nonalcohol steatohepatitis (NASH) with liver fibrosis.
Verwenden
6-Ethylchenodeoxycholic Acid is a derivative of the bile acid Chenodeoxycholic Acid (C291900). 6-Ethylchenodeoxycholic Acid is a potent activator of the farnesoid X nuclear receptor which reduces liver fat and fibrosis in animal models of fatty liver disease.
Definition
ChEBI: A dihydroxy-5beta-cholanic acid that is chenodeoxycholic acid carrying an additional ethyl substituent at the 6alpha-position. A semi-synthetic bile acid which acts as a farnesoid X receptor agonist and is used for treatme t of primary biliary cholangitis.
Synthese
The synthesis of obeticholic acid was initiated from commercial 3|á-hydroxy-7-keto-5|?-cholan-24-oic acid (138). Fischer esterification of 138 provided methyl ester 139, which was treated with trimethylsilyl chloride and triethylamine to protect the secondary alcohol. Reaction of the protected alcohol with lithium diisopropylamine and trimethylsilyl chloride gave silyl enol ether 140. Aldol condensation with acetaldehyde and boron trifluoride etherate followed by saponification of the methyl ester produced enone 141. Hydrogenation of the olefin followed by heating to reflux to epimerize the resulting ethyl group produced the |á-ethyl ketone 142 in 62% yield from compound 138. Reduction of the ketone in 142 with sodium borohydride and subsequent crystallization from phosphoric acid and water gave obeticholic acid (XIV) in 90% yield.
Enzyminhibitor
This semisynthetic bile acid analogue (FW = 420.63 g/mol; CAS 459789- 99-2), also named INT-747, 6α-ethyl-chenodeoxycholate, and (3α,5β,6α, 7α)-6-ethyl-3,7-dihydroxycholan-24-oic acid, is an analogue of the naturally occurring bile acid (FW = 392.57 g/mol; CAS 474-25-9). The latter is synthesized in the liver, where it conjugated to form taurochenodeoxycholate and glycol-chenodeoxycholate, reducing its pKa and increasing retention in the gastrointestinal tract, until reabsorption by the ileum. Chenodeoxycholate is the most active physiological ligand known for the farnesoid X receptor, or FXR (encoded by the NR1H4 gene in humans) that translocates to the nucleus, dimerizes, and binds to hormone response elements. Obeticholic acid reduces bacterial translocation and invasion in cirrhotic rats by restoring intestinal barrier integrity (through increased expression of tight junction proteins) and by inhibiting inflammation. Obeticholate likewise up-regulated expression of the FXR-associated gene small heterodimer partner (SHP).
Lager
+4°C
Einzelnachweise
1) Fiorucci?et al.?(2005),?Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis; J. Pharmacol. Exp. Ther.,?313?604 2) Rizzo?et al. (2006),?The farnesoid X receptor promotes adipocyte differentiation and regulates adipose cell function in vivo;?Mol. Pharmacol.,?70?1164 3) Maneschi?et al.?(2013),?FXR activation normalizes insulin sensitivity in visceral preadipocytes of a rabbit model of MetS; J. Endocrinol.,?218?215 4) Carr and Reid (2015),?FXR agonists as therapeutic agents for non-alcoholic fatty liver disease; Curr. Atheroscler. Rep,?17?500 5) Jahn?et al. (2016),?Non-Alcoholic Steatohepatitis: From Pathophysiology to Novel Therapies; Dig. Dis.,?34?356 6) Hirschfield?et al. (2015),?Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid; Gastroenterology,?148?751

Obeticholic Acid Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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