Bedaquiline

Structural formula
General
Non-proprietary name	Bedaquiline
other names	(1 R , 2 S ) -1- (6-Bromo-2-methoxyquinolin-3-yl) -4-dimethylamino-2- (naphthalen-1-yl) -1-phenylbutan-2-ol R207910 TMC-207
Molecular formula	C 32 H 31 BrN 2 O 2
External identifiers / databases
CAS number 843663-66-1 PubChem 5388906 ChemSpider 4534966 DrugBank DB08903 Wikidata Q1257318
Drug information
ATC code	J04 AK05
Drug class	Tuberculostatics
properties
Molar mass	555.51 g mol −1
Physical state	firmly
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS hazard labeling no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Bedaquiline is a drug used to treat tuberculosis ( tuberculostatic ). It is used in particular in combination therapies against multi-resistant tuberculosis bacteria .

Chemically, it is a compound from the group of diarylquinolines .

history

Bedaquiline was approved in the USA at the end of 2012 and in the EU in 2014 , making it the first new tuberculostatic drug in decades. Rifabutin was last added in Germany in 1994.

Bedaquiline emerged from a screening program with more than 70,000 compounds. In 2015, the researchers Koen Andries and Jérôme Guillemont received the European Inventor Award for this .

properties

Bedaquiline has two stereogenic centers . Investigations of the minimum inhibitory concentrations (MIC) of the various isomers showed that the (1 R , 2 S ) stereoisomer (= bedaquiline) was the most effective (its MIC against Mycobacterium tuberculosis was between 0.03 and 0.12 µg / ml; the MIC ₉₀ was 0.06 µg / ml. In comparison, the MIC ₉₀ for the (1 S , 2 R ) isomer was 8.8 µg / ml, that of the mixture of both 1.8 µg / ml and that of the (1 R , 2 R / 1 S , 2 S ) -diastereomer mixture 44 µg / ml). This in-vitro finding is the same as that from computer-aided attachment models. Enantiomerically pure bedaquiline is obtained by controlled crystallization using an enantiomeric organophosphate as the conclusion of the multi-stage synthesis, in which a mixture of the stereoisomers is first formed.

The salt (1: 1) of fumaric acid , bedaquiline fumarate , is used medicinally . The substance is a white to almost white, non-hygroscopic powder that is practically insoluble in aqueous media over a wide pH range , but soluble in a number of organic solvents.

Mechanism of action

Bedaquiline inhibits the ATP synthase of mycobacteria by binding to the c-subunit of the enzyme. The ATP synthase is an important enzyme in the cellular energy metabolism of the mycobacteria. Their inhibition leads to bactericidal effects in both dividing and non-dividing pathogens. Bedaquiline is the only therapeutically used antibiotic with this mechanism of action. The minimum inhibitory concentration ( MIC ) for M. tuberculosis are 0.03 μg / mL (for the MIC ₅₀ ) and 0.06 μg / mL (for the MIC ₉₀ ).

Pharmacokinetics

The main route of degradation is N - demethylation by CYP3A4 . It is assumed that the resulting metabolite (M2) does not contribute significantly to the effectiveness. Bedaquiline is excreted in the faeces .

Side effects

Bedaquiline is both hepato- and cardiotoxic in that it increases liver enzymes ( AST , ALT ) and bilirubin , and increases the QT interval in the heart . The most common side effects observed in the studies were nausea , arthralgia , headache, vomiting, and dizziness.

Finished medicinal products

Sirturo (manufacturer: Janssen Pharmaceutica )

See also

• Delamanid

Individual evidence

1. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
2. ↑ ^{a b c} Ashish Kumar Kakkar, Neha Dahiya: Bedaquiline for the treatment of resistant tuberculosis: Promises and pitfalls . In: Tuberculosis . tape 94 , no. 4 , 2014, p. 357-362 , doi : 10.1016 / j.tube.2014.04.001 .
3. ↑ ^{a b} Mageshwaran Lakshmanan, Alphienes Stanley Xavier: Bedaquiline - The first ATP synthase inhibitor against multidrug resistant tuberculosis . In: Journal of Young Pharmacists . tape 5 , no. 4 , 2013, p. 112–115 , doi : 10.1016 / j.jyp.2013.12.002 .
4. ↑ New drugs for tuberculosis , November 20, 2016.
5. ↑ ^{a b} Entry on Bedaquiline. In: Römpp Online . Georg Thieme Verlag, accessed on November 25, 2016.
6. ↑ K. Andries et al .: A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis . In: Science . tape 307 (2005) , pp. 223-227 , doi : 10.1126 / science.1106753 .
7. ↑ Koul, A., Dendouga, N., Vergauwen, K. et al .: Diarylquinolines target subunit c of mycobacterial ATP synthase . In: Nature Chemical Biology . tape 3 (2007) , pp. 323-324 , doi : 10.1038 / nchembio884 .
8. ↑ Marc R. de Jonge, Luc HM Koymans, Jérôme EG Guillemont, Anil Koul, Koen Andries: A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910 . In: Proteins Structure Function and Bioinformatics . May 1, 2007, doi : 10.1002 / prot.21376 .
9. ↑ ^{a b c d} CHMP assessment report - Sirturo, dated December 13, 2013.
10. ↑ External identifiers from or database links to Bedaquilinfumarat : CAS Number: 845533-86-0, EC number: 805-637-5, ECHA -InfoCard: 100232531 , PubChem : 24812732 , ChemSpider : 28528191 , Wikidata : Q27139886 .
11. Jump up ↑ Ke Liu, Feng Li, Jie Lu, Shinlan Liu, Kenneth Dorko, Wen Xie, Xiaochao Ma: Bedaquiline Metabolism: Enzymes and Novel Metabolites . In: Drug Metabolism and Disposition . tape 42 , no. 5 , May 1, 2014, p. 863-866 , doi : 10.1124 / dmd.113.056119 .

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