Obeticholic acid

Identification

Name
Obeticholic acid
Accession Number
DB05990
Type
Small Molecule
Groups
Approved
Description

Obeticholic acid is a farnesoid-X receptor (FXR) agonist and is used to treat a number of liver diseases. [1] Obeticholic acid has been granted accelerated approval to treat primary biliary cholangitis in combination with ursodeoxycholic acid. [1] Approval is limited to monotherapy in patient's who are intolerant to ursodeoxycholic acid, or in combination with ursodeoxycholic acid in adults who have not responded adequately to ursodeoxyholic acid alone. [1] Obeticholic acid given orally, binds to the farnesoid X receptor (FXR), a receptor found in the nucleus of cells in the liver and intestine. FXR is a key regulator of bile acid metabolic pathways. Obeticholic acid increases bile flow from the liver and suppresses bile acid production in the liver, thus reducing the exposure of the liver to toxic levels of bile acids.

Structure
Thumb
Synonyms
  • 6-ECDCA
  • 6-Ethyl-CDCA
  • 6-ethylchenodeoxycholic acid
  • 6alpha-Ethyl-chenodeoxycholic acid
  • 6α-ethylchenodeoxycholic acid
External IDs
DSP-1747 / INT 747 / INT-747 / INT747
Product Ingredients
Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
OcalivaTablet, film coated5 mg/1OralIntercept Pharmaceuticals2016-05-27Not applicableUs
OcalivaTablet10 mgOralIntercept Pharmaceuticals2017-05-26Not applicableCanada
OcalivaTablet, film coated10 mg/1OralIntercept Pharmaceuticals2016-05-27Not applicableUs
OcalivaTablet5 mgOralIntercept Pharmaceuticals2017-05-26Not applicableCanada
Approved Generic Prescription Products
Not Available
Approved Over the Counter Products
Not Available
Unapproved/Other Products
Not Available
International/Other Brands
Not Available
Brand mixtures
Not Available
Categories
UNII
0462Z4S4OZ
CAS number
459789-99-2
Weight
Average: 420.6252
Monoisotopic: 420.323959896
Chemical Formula
C26H44O4
InChI Key
ZXERDUOLZKYMJM-ZWECCWDJSA-N
InChI
InChI=1S/C26H44O4/c1-5-17-21-14-16(27)10-12-26(21,4)20-11-13-25(3)18(15(2)6-9-22(28)29)7-8-19(25)23(20)24(17)30/h15-21,23-24,27,30H,5-14H2,1-4H3,(H,28,29)/t15-,16-,17-,18-,19+,20+,21+,23+,24-,25-,26-/m1/s1
IUPAC Name
(4R)-4-[(1S,2S,5R,7S,8R,9R,10S,11S,14R,15R)-8-ethyl-5,9-dihydroxy-2,15-dimethyltetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadecan-14-yl]pentanoic acid
SMILES
[H][C@@](C)(CCC(O)=O)[C@@]1([H])CC[C@@]2([H])[C@]3([H])[C@]([H])(O)[C@]([H])(CC)[C@]4([H])C[C@]([H])(O)CC[C@]4(C)[C@@]3([H])CC[C@]12C

Pharmacology

Indication

Investigated for use/treatment in liver disease. Obeticholic acid was approved as an orphan drug based on its reduction in the level of the biomarker alkaline phosphatase as a surrogate endpoint for clinical benefit. It is indicated for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA. Additional studies are being required to prove its clinical benefit.

Structured Indications
Pharmacodynamics

In Trial 1, ALP reduction was observed to plateau at approximately 3 months in most patients treated with Obeticholic acid 5 mg once daily. Increasing the dosage of Obeticholic acid to 10 mg once daily based on tolerability and response provided additional reduction in ALP in the majority of patients.

Mechanism of action

Obeticholic acid (also known as INT-747), is a potent, orally bioavailable farnesoid X receptor (FXR) agonist. The key role of the farnesoid X receptor (FXR) as a regulator of bile and cholesterol metabolism in the liver, with preclinical data from numerous studies providing strong rationale for the advancement of FXR agonists as hepatoprotective therapeutics in chronic liver disease.

TargetActionsOrganism
ABile acid receptor
agonist
Human
Absorption

Peak plasma concentrations (Cmax) of obeticholic acid occurred at a median time (Tmax) of approximately 1.5 hours. Coadministration with food did not alter the extent of absorption of obeticholic acid.

Volume of distribution

Vd = 618 L

Protein binding

Obeticholic acid and it's conjugates bind to human plasma protein at a rate of 99% or higher.

Metabolism

Obeticholic acid is conjugated with glycine or taurine in the liver and secreted into bile. These glycine and taurine conjugates of obeticholic acid are absorbed in the small intestine leading to enterohepatic recirculation.

Route of elimination

The principal route of elimination is fecal where about 87% of the dose was excreted in feces through biliary secretion. Less than 3% of the dose was excreted in the urine.

Half life

Steady state half life: ~4 days

Clearance

Not found

Toxicity

LD50: not known. Overdosage of Obeticholic acid could yield in dose-dependent increase in the incidence of liver-related adverse reactions including portal hypertension, ascites, jaundice and elevation in liver biochemical tests. Severe Pruritus.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
TizanidineThe serum concentration of Tizanidine can be increased when it is combined with Obeticholic acid.Approved
Food Interactions
Not Available

References

Synthesis Reference
Not Available
General References
  1. Markham A, Keam SJ: Obeticholic Acid: First Global Approval. Drugs. 2016 Aug;76(12):1221-6. doi: 10.1007/s40265-016-0616-x. [PubMed:27406083 ]
  2. fda advisory committee [Link]
  3. product info [Link]
  4. product info [Link]
  5. MSDS [Link]
External Links
KEGG Drug
D09360
KEGG Compound
C15636
ChemSpider
394730
BindingDB
21675
ChEBI
43602
ChEMBL
CHEMBL566315
HET
CHC
Wikipedia
Obeticholic_acid
ATC Codes
A05AA04 — Obeticholic acid
AHFS Codes
Not Available
PDB Entries
Not Available
FDA label
Download (5.07 MB)
MSDS
Not Available

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingBasic SciencePrimary Biliary Cirrhosis (PBC)1
1CompletedBasic ScienceHealthy Volunteers1
1CompletedBasic ScienceHepatic Impairment1
1RecruitingBasic ScienceBMI >30 kg/m21
2Active Not RecruitingTreatmentNonalcoholic Steatohepatitis1
2CompletedBasic ScienceBMI >30 kg/m2 / Gallstone formation1
2CompletedBasic SciencePrimary Biliary Cirrhosis (PBC)1
2CompletedTreatmentChronic Functional Diarrhea / Primary Bile Acid Malabsorption / Secondary Bile Acid Malabsorption1
2CompletedTreatmentFatty Liver / Type 2 Diabetes Mellitus1
2CompletedTreatmentLiver Cirrhosis, Biliary2
2CompletedTreatmentNonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic Steatohepatitis (NASH)1
2RecruitingTreatmentAlcoholic Hepatitis (AH)1
2RecruitingTreatmentLipodystrophy, Familial Partial1
3Active Not RecruitingTreatmentPrimary Biliary Cirrhosis (PBC)1
3RecruitingTreatmentNon Alcoholic Steatohepatitis (NASH)1
4RecruitingTreatmentLiver Cirrhosis, Biliary1
Not AvailableRecruitingOtherAlcohol Consumption1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral10 mg
TabletOral5 mg
Tablet, film coatedOral10 mg/1
Tablet, film coatedOral5 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7138390 No2002-11-162022-11-16Us
US9238673 No2013-06-172033-06-17Us
US8058267 No2002-02-212022-02-21Us
US8377916 No2002-02-212022-02-21Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.011 mg/mLALOGPS
logP3.5ALOGPS
logP4.52ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)4.6ChemAxon
pKa (Strongest Basic)-0.16ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area77.76 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity118.35 m3·mol-1ChemAxon
Polarizability49.74 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted LC-MS/MS Spectrum - 10V, PositivePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 20V, PositivePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 40V, PositivePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 10V, NegativePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 20V, NegativePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 40V, NegativePredicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as dihydroxy bile acids, alcohols and derivatives. These are compounds containing or derived from a bile acid or alcohol, and which bears exactly two carboxylic acid groups.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Bile acids, alcohols and derivatives
Direct Parent
Dihydroxy bile acids, alcohols and derivatives
Alternative Parents
7-hydroxysteroids / 3-alpha-hydroxysteroids / Secondary alcohols / Cyclic alcohols and derivatives / Monocarboxylic acids and derivatives / Carboxylic acids / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Dihydroxy bile acid, alcohol, or derivatives / 3-hydroxysteroid / Hydroxysteroid / 3-alpha-hydroxysteroid / 7-hydroxysteroid / Cyclic alcohol / Secondary alcohol / Monocarboxylic acid or derivatives / Carboxylic acid / Carboxylic acid derivative
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
cholanoid (CHEBI:43602 )

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Zinc ion binding
Specific Function
Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxyla...
Gene Name
NR1H4
Uniprot ID
Q96RI1
Uniprot Name
Bile acid receptor
Molecular Weight
55913.915 Da
References
  1. Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney PR, Morelli A, Parks DJ, Willson TM: 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002 Aug 15;45(17):3569-72. [PubMed:12166927 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Very long chain acyl-coa hydrolase activity
Specific Function
Involved in bile acid metabolism. In liver hepatocytes catalyzes the second step in the conjugation of C24 bile acids (choloneates) to glycine and taurine before excretion into bile canaliculi. The...
Gene Name
BAAT
Uniprot ID
Q14032
Uniprot Name
Bile acid-CoA:amino acid N-acyltransferase
Molecular Weight
46298.865 Da
References
  1. article [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
Drug created on November 18, 2007 11:29 / Updated on September 01, 2017 11:26