Identification

Name
Bedaquiline
Accession Number
DB08903
Type
Small Molecule
Groups
Approved
Description

Bedaquiline is a bactericidal antimycobacterial drug. Chemically it is a diarylquinoline. FDA approved on December 28, 2012.

Structure
Thumb
Synonyms
  • 1-(6-Bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-naphthalen-1-yl-1-phenyl-butan-2-ol
  • Bedaquilina
  • Bedaquilinum
  • R 207910
  • TMC 207
  • TMC-207
  • TMC207
External IDs
AIDS222089 / R-207910 / R207910 / TMC207
Product Ingredients
IngredientUNIICASInChI Key
Bedaquiline FumarateP04QX2C1A5845533-86-0ZLVSPMRFRHMMOY-WWCCMVHESA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SirturoTablet100 mgOralJanssen Cilag International Nv2014-03-05Not applicableEu
SirturoTablet100 mg/1OralJanssen, Lp2012-12-28Not applicableUs
SirturoTablet100 mgOralJanssen Cilag International Nv2014-03-05Not applicableEu
Categories
UNII
78846I289Y
CAS number
843663-66-1
Weight
Average: 555.505
Monoisotopic: 554.156890893
Chemical Formula
C32H31BrN2O2
InChI Key
QUIJNHUBAXPXFS-XLJNKUFUSA-N
InChI
InChI=1S/C32H31BrN2O2/c1-35(2)19-18-32(36,28-15-9-13-22-10-7-8-14-26(22)28)30(23-11-5-4-6-12-23)27-21-24-20-25(33)16-17-29(24)34-31(27)37-3/h4-17,20-21,30,36H,18-19H2,1-3H3/t30-,32-/m1/s1
IUPAC Name
(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
SMILES
COC1=NC2=C(C=C(Br)C=C2)C=C1[C@@H](C1=CC=CC=C1)[C@@](O)(CCN(C)C)C1=CC=CC2=C1C=CC=C2

Pharmacology

Indication

Bedaquiline is indicated as part of combination therapy in adults (≥ 18 years) with pulmonary multi-drug resistant tuberculosis (MDR-TB).

Associated Conditions
Pharmacodynamics

Bedaquiline is primarily subjected to oxidative metabolism leading to the formation of N-monodesmethyl metabolite (M2). M2 is not thought to contribute significantly to clinical efficacy given its lower average exposure (23% to 31%) in humans and lower antimycobacterial activity (4 to 6-fold lower) compared to the parent compound. M2 concentrations appeared to correlate with QT prolongation. Bedaquiline inhibits mycobacterial TB at a minimal inhibitory concentration (MIC) from 0.002-0.06 μg/ml and with a MIC50 of 0.03 μg/ml. Furthermore, bacteria that have smaller ATP stores (usually in dormant, nonreplicating bacilli) are more susceptible to bedaquiline.

Mechanism of action

Bedaquiline is a diarylquinoline antimycobacterial drug that inhibits the proton pump of mycobacterial ATP (adenosine 5'-triphosphate) synthase, an enzyme that is essential for the generation of energy in Mycobacterium tuberculosis. Bacterial death occurs as a result of bedaquiline.

TargetActionsOrganism
AATP synthase subunit c
inhibitor
Mycobacterium tuberculosis
Absorption

Tmax, oral dose = 5 hours; Food increases the oral bioavailability. AUC increases proportionally up to the highest dose studied in healthy volunteers. When 400 mg of bedaquiline is administered once daily for a week, the peak plasma concentration (Cmax) is 5.5 μg/ml and an AUC of 64.75 μgh/ml.

Volume of distribution

Vd, central compartment = 164 L

Protein binding

>99.9 bound to plasma proteins.

Metabolism

Bedaquiline is hepatically metabolized. The main enzyme involved is CYP3A4 which metabolizes bedaquiline into the N-monodesmethyl metabolite (M2). This metabolite is 4 to 6-times less active in terms of antimycobacterial potency.

Route of elimination

Bedaquiline is primarily elimination in the feces. The urinary excretion of unchanged bedaquiline was < 0.001% of the dose in clinical studies, indicating that renal clearance of unchanged drug is insignificant.

Half life

Terminal elimination half-life, bedaquiline and M2 = 5.5 months. This long half-life suggests slow release of bedaquiline and M2 from peripheral tissues.

Clearance
Not Available
Toxicity

The most common adverse reactions reported in ≥10% of patients treated with bedaquiline are nausea, arthralgia, and headache.

Affected organisms
  • Mycobacterium tuberculosis
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when Bedaquiline is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Bedaquiline is combined with (S)-Warfarin.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Bedaquiline.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Bedaquiline.
5-androstenedioneThe metabolism of Bedaquiline can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Bedaquiline can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Bedaquiline.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Bedaquiline.
AbexinostatThe risk or severity of QTc prolongation can be increased when Bedaquiline is combined with Abexinostat.
AbirateroneThe metabolism of Bedaquiline can be decreased when combined with Abiraterone.
Food Interactions
  • When administered with food, relative bioavailability increases 2-fold

References

General References
  1. Matteelli A, Carvalho AC, Dooley KE, Kritski A: TMC207: the first compound of a new class of potent anti-tuberculosis drugs. Future Microbiol. 2010 Jun;5(6):849-58. doi: 10.2217/fmb.10.50. [PubMed:20521931]
External Links
KEGG Drug
D09872
KEGG Compound
C14122
PubChem Compound
5388906
PubChem Substance
175427143
ChemSpider
4534966
ChEBI
72292
ChEMBL
CHEMBL376488
HET
BQ1
RxList
RxList Drug Page
Wikipedia
Bedaquiline
ATC Codes
J04AK05 — Bedaquiline
PDB Entries
4v1f
FDA label
Download (505 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedOtherTuberculosis Infection1
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) / Tuberculosis Infection2
1CompletedTreatmentModerate Hepatic Impairment1
1CompletedTreatmentTuberculosis Infection2
1, 2RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections / Tuberculosis Infection1
2Active Not RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections / Tuberculosis Infection1
2Active Not RecruitingTreatmentPulmonary Multi-Drug Resistant Tuberculosis (MDR-TB) / Tuberculosis, Multidrug Resistant1
2CompletedTreatmentPulmonary Tuberculosis (TB)3
2CompletedTreatmentTuberculosis Infection4
2RecruitingTreatmentDrug-resistant Tuberculosis / Extensively Drug Resistant Tuberculosis / Multi-Drug Resistant Tuberculosis / Pulmonary Tuberculosis (TB) / Tuberculosis Infection / Tuberculosis, Multidrug Resistant1
2RecruitingTreatmentLeprosy, Multibacillary1
2RecruitingTreatmentTuberculosis, Multidrug Resistant1
2, 3Not Yet RecruitingTreatmentPulmonary Tuberculosis (TB)1
2, 3RecruitingTreatmentExtensively Drug Resistant Tuberculosis / Pulmonary Tuberculosis (TB) / Tuberculosis, Multidrug Resistant1
2, 3RecruitingTreatmentExtensively Drug Resistant Tuberculosis / Tuberculosis Infection / Tuberculosis, Multidrug Resistant1
3Active Not RecruitingTreatmentPulmonary Tuberculosis (TB)1
3RecruitingTreatmentExtensively Drug Resistant Tuberculosis / Multi-Drug Resistant Tuberculosis / Pre-XDR-TB / Pulmonary Tuberculosis (TB) / Tuberculosis Infection / Tuberculosis, Multidrug Resistant1
3RecruitingTreatmentMulti-Drug Resistant Tuberculosis1
3RecruitingTreatmentTuberculosis, Multidrug Resistant1
4RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections1
Not AvailableApproved for MarketingNot AvailableTuberculosis Infection1
Not AvailableRecruitingNot AvailableTuberculosis Infection1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral100 mg
TabletOral100 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7498343No2004-10-022024-10-02Us
US8546428No2009-03-192029-03-19Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityInsoluble FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.000193 mg/mLALOGPS
logP6.37ALOGPS
logP7.13ChemAxon
logS-6.5ALOGPS
pKa (Strongest Acidic)13.61ChemAxon
pKa (Strongest Basic)8.91ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area45.59 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity154.02 m3·mol-1ChemAxon
Polarizability57.29 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9811
Blood Brain Barrier+0.8854
Caco-2 permeable+0.6526
P-glycoprotein substrateSubstrate0.7553
P-glycoprotein inhibitor IInhibitor0.7137
P-glycoprotein inhibitor IIInhibitor0.5998
Renal organic cation transporterNon-inhibitor0.554
CYP450 2C9 substrateNon-substrate0.814
CYP450 2D6 substrateNon-substrate0.5081
CYP450 3A4 substrateSubstrate0.8225
CYP450 1A2 substrateInhibitor0.6983
CYP450 2C9 inhibitorNon-inhibitor0.6497
CYP450 2D6 inhibitorInhibitor0.5348
CYP450 2C19 inhibitorNon-inhibitor0.5469
CYP450 3A4 inhibitorNon-inhibitor0.6535
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5292
Ames testNon AMES toxic0.6998
CarcinogenicityNon-carcinogens0.9055
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.7887 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9607
hERG inhibition (predictor II)Inhibitor0.6476
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

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

Taxonomy

Description
This compound belongs to the class of organic compounds known as stilbenes. These are organic compounds containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are derived from the common phenylpropene (C6-C3) skeleton building block. The introduction of one or more hydroxyl groups to a phenyl ring lead to stilbenoids.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Stilbenes
Sub Class
Not Available
Direct Parent
Stilbenes
Alternative Parents
Quinolones and derivatives / Haloquinolines / Phenylbutylamines / Naphthalenes / Alkyl aryl ethers / Aralkylamines / Aryl bromides / Pyridines and derivatives / Heteroaromatic compounds / 1,3-aminoalcohols
show 7 more
Substituents
Stilbene / Quinolone / Haloquinoline / Phenylbutylamine / Quinoline / Naphthalene / Alkyl aryl ether / Aralkylamine / Pyridine / Aryl bromide
show 23 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
tertiary alcohol, organobromine compound, tertiary amino compound, aromatic ether, quinolines, naphthalenes (CHEBI:72292)

Targets

Kind
Protein
Organism
Mycobacterium tuberculosis
Pharmacological action
Yes
Actions
Inhibitor
General Function
F(1)F(0) ATP synthase produces ATP from ADP in the presence of a proton or sodium gradient. F-type ATPases consist of two structural domains, F(1) containing the extramembraneous catalytic core and F(0) containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation.
Specific Function
Lipid binding
Gene Name
atpE
Uniprot ID
P9WPS1
Uniprot Name
ATP synthase subunit c
Molecular Weight
8055.41 Da
References
  1. Koul A, Dendouga N, Vergauwen K, Molenberghs B, Vranckx L, Willebrords R, Ristic Z, Lill H, Dorange I, Guillemont J, Bald D, Andries K: Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol. 2007 Jun;3(6):323-4. Epub 2007 May 13. [PubMed:17496888]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
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 performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da

Drug created on June 10, 2013 15:32 / Updated on November 02, 2018 08:32