| Identification | Back Directory | [Name]
Bedaquiline (fuMarate) | [CAS]
845533-86-0 | [Synonyms]
R 403323
TMC207 fumarate
R207910 fumarate
TMC-207;TMC207;TMC 207
Bedaquiline (fuMarate)
Bedaquiline Fumarate salt
(1R,2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol
(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol fumarate
(1R,2S)-1-(6-Bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthyl)-1-phenyl-2-butanol (2E)-2-butenedioate (1:1)
(1R,2S)-1-(6-broMo-2-Methoxyquinolin-3-yl)-4-(diMethylaMino)-2-naphthalen-1-yl-1-phenylbutan-2-ol,(E)-but-2-enedioic acid | [Molecular Formula]
C36H35BrN2O6 | [MDL Number]
MFCD28167761 | [MOL File]
845533-86-0.mol | [Molecular Weight]
671.59 |
| Chemical Properties | Back Directory | [storage temp. ]
Inert atmosphere,Room Temperature | [solubility ]
DMSO : 100 mg/mL (148.90 mM; Need ultrasonic)H2O : < 0.1 mg/mL (insoluble) | [form ]
Powder | [color ]
White to off-white | [InChIKey]
ZLVSPMRFRHMMOY-KZDJUSSONA-N | [SMILES]
C(/C(=O)O)=C\C(=O)O.[C@](C1=CC=CC2C=CC=CC1=2)(O)(CCN(C)C)[C@H](C1C=CC=CC=1)C1=CC2C=C(Br)C=CC=2N=C1OC |&1:8,25,r| |
| Hazard Information | Back Directory | [Description]
Bedaquiline fumarate (BQF,845533-86-0) is an FDA-approved antituberculosis drug that targets the enzyme ATP synthase. It is a fumarate salt prepared from equimolar amounts of bedaquiline and fumaric acid. It can be used in combination therapy for the treatment of multidrug-resistant tuberculosis in the lungs of adults (18 years of age and older). The new BQF microemulsion dosage form of BQF has improved oral bioavailability over the previous formulation, and the BQF microemulsion is cytocompatible with significantly higher cellular uptake than the control group at the highest concentration of 500 μg/ml, which could lead to further use in the effective treatment of multidrug-resistant tuberculosis[1].
| [Definition]
ChEBI: A fumarate salt prepared from equimolar amounts of bedaquiline and fumaric acid. It is used in combination therapy for the treatment of pulmonary multi-drug resistant tuberculosis by inhibition of ATP synthase, an enzyme essential for the replication of th
mycobacteria. | [Clinical Use]
Bedaquiline fumarate is a diarylquinone drug developed by Janssen Pharmaceutical which is
marketed under the trade name Sirturo ®. The drug, which was approved in 2012 for the treatment of
multidrug-resistant tuberculosis (MDR-TB), was developed in partnership with Johnson & Johnson and
represents the first new tuberculosis therapy approved in over four decades. Bedaquiline is the first
member of a new class of diarylquinone compounds whose mechanism of action inhibits Mycobaterium
tuberculosis ATP synthase which deprives bacterium of energy. | [Synthesis]
Of the relatively few synthetic approaches to bedaquiline (or its fumarate salt) that have been
reported, the most likely process-scale route is that described by Porstmann and co-workers from
Janssen Pharmaceutical, and this route is outlined in the scheme. The synthesis was initiated by first
freebasing commercially available dimethylaminoketone 31 with sodium hydroxide to provide naphthylone 32 in nearly quantitative yield. Subjection of commercially available quinoline 33 to LDA
removed the benzyllic proton within this system and subsequent trap with naphthylone 32 gave rise to a
mixture of diastereomers whereby the major diastereomer obtained from this reaction corresponded to
the bedaquiline geometry. The minor diastereomer was resolved through multiple recrystallizations and
seeding techniques. This racemate of the major diastereomer subsequently underwent a chiral
resolution upon treatment with BINAP derivative 34 in refluxing DMSO and then upon cooling and
subjection to aqueous base in warm toluene furnished bedaquiline 35 bearing the requisite (R,S)-
configuration of the two vicinal chiral centers corresponding to that of the drug. The overall yield of the
conversion of 33 to enantiopure 35 was 39%. Aminoquinolinol 35 was then prepared as the
corresponding fumarate salt upon treatment with fumaric acid in the presence of isopropanol, and this
salt formation delivered bedaquiline fumarate (VI) in 82% yield.
| [Drug interactions]
Potentially hazardous interactions with other drugs
Antibacterials: concentration possibly increased
by ciprofloxacin, clarithromycin and erythromycin
- avoid concomitant use if for more than 14 days;
avoid with moxifloxacin; concentration possibly
reduced by rifampicin - avoid; possibly increased risk
of ventricular arrhythmias with clofazimine.
Antiepileptics: concentration possibly reduced by
carbamazepine, fosphenytoin and phenytoin - avoid.
Antivirals: AUC increased by ritonavir, use with
caution, avoid in combination with lopinavir. | [Metabolism]
Bedaquiline is metabolised mainly by the hepatic
CYP3A4 isoenzyme to the N-monodesmethyl metabolite
(M2), which is 4-6 times less active than the parent
compound.
Bedaquiline is excreted mainly in the faeces. | [References]
[1] VISHWAS P PARDHI. Bedaquiline fumarate microemulsion: formulation optimization, rheological characterization and in vitro studies.[J]. Nanomedicine (London, England), 2022, 17 21: 1529-1546. DOI:10.2217/nnm-2022-0132. |
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