BEDAQUILINE FUMARATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C32H31BrN2O2.C4H4O4
Molecular Weight	671.577
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

SMILES

OC(=O)\C=C\C(O)=O.COC1=NC2=CC=C(Br)C=C2C=C1[C@@H](C3=CC=CC=C3)[C@@](O)(CCN(C)C)C4=C5C=CC=CC5=CC=C4

InChI

InChIKey=ZLVSPMRFRHMMOY-WWCCMVHESA-N

InChI=1S/C32H31BrN2O2.C4H4O4/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;5-3(6)1-2-4(7)8/h4-17,20-21,30,36H,18-19H2,1-3H3;1-2H,(H,5,6)(H,7,8)/b;2-1+/t30-,32-;/m1./s1

HIDE SMILES / InChI

Molecular Formula	C4H4O4
Molecular Weight	116.0722
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	1
Optical Activity	NONE

Molecular Formula	C32H31BrN2O2
Molecular Weight	555.505
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Bedaquiline (trade name Sirturo, code names TMC207 and R207910) is a diarylquinoline anti-tuberculosis drug, which was discovered by a team led by Koen Andries at Janssen Pharmaceutica. When it was approved by the FDA on the 28th December 2012, it was the first new medicine to fight TB in more than forty years, and is specifically approved to treat multi-drug-resistant tuberculosis. 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.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
ATP synthase subunit c 2	Inhibitor 8,297
ATP synthase subunit c 2	Inhibitor 8,297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Tuberculosis, multidrug-resistant 5	Curative		Approved 8,429	SIRTURO

C_max

Value	Dose	Co-administered	Analyte	Population
2.547 mg/L	300 mg single, oral		BEDAQUILINE plasma	Homo sapiens
3.755 mg/L	450 mg single, oral		BEDAQUILINE plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
38.737 mg × h/L	300 mg single, oral		BEDAQUILINE plasma	Homo sapiens
64.53 mg × h/mL	450 mg single, oral		BEDAQUILINE plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
24 h	300 mg single, oral		BEDAQUILINE plasma	Homo sapiens
24 h	450 mg single, oral		BEDAQUILINE plasma	Homo sapiens

F_unbound

Value	Dose	Analyte	Population
0.01%	300 mg single, oral	BEDAQUILINE plasma	Homo sapiens
0.01%	450 mg single, oral	BEDAQUILINE plasma	Homo sapiens
0.01%	400 mg 1 times / day unknown, oral	BEDAQUILINE plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
400 mg 4 times / week multiple, oral Overdose	unhealthy, 21 years n = 1
400 \| 200 mg\|mg 1\|3 times / day\|week multiple, oral (complex) Recommended	unhealthy, 34 years n = 79	Other AEs: Death...

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AEs

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AE	Significance	Dose	Population
Death	11.4%	400 \| 200 mg\|mg 1\|3 times / day\|week multiple, oral (complex) Recommended	unhealthy, 34 years n = 79

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inhibitor 1,587 inducer 781	inhibitor 1,767 inducer 389	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1,524 CYP2A6 707 CYP2C8 911 CYP2C19 1,478 CYP2E1 882 CYP3A4/5 278 CYP4A 19 P-gp 1,461	P-gp 1,537	CYP1A2 701 CYP2C19 293

Drug as perpetrator

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Target	Modality	Activity
CYP1A2 1,692	inducer 1,573	no
CYP1A2 1,692	inhibitor 3,277	no
CYP2A6 739	inhibitor 3,277	no
CYP2C19 1,553	inducer 1,573	no
CYP2C19 1,553	inhibitor 3,277	no

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Drug as victim

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Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A4 1,737	substrate 3,367	major		yes (co-administration study)
P-gp 1,537	substrate 3,367	yes

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:72292	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:72292
MolPort	MolPort-035-683-920	https://www.molport.com/shop/molecule-link/MolPort-035-683-920
ZINC	ZINC000004655029	http://zinc15.docking.org/substances/ZINC000004655029

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PubMed

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Title	Date	PubMed
Bactericidal activity of the diarylquinoline TMC207 against Mycobacterium tuberculosis outside and within cells.	2010 Sep	20732832

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Patents

Sample Use Guides

In Vivo Use Guide

400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks with food. Swallow SIRTURO (bedaquiline) tablets whole with water.

Route of Administration: Oral

In Vitro Use Guide

Modification of the atpE target gene, and/or upregulation of the MmpS5-MmpL5 efflux pump have been associated with increased bedaquiline MIC values in isolates of M. tuberculosis. Target-based mutations generated in preclinical studies lead to 8- to 133-fold increases in bedaquiline MIC, resulting in MICs ranging from 0.25 to 4.0 ug/mL. Efflux-based mutations have been seen in preclinical and clinical isolates. These lead to 2- to 8-fold increases in bedaquiline MICs, resulting in bedaquiline MICs ranging from 0.25 to 0.50 ug/ mL.

Substance Class	Chemical
Record UNII	P04QX2C1A5
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

BEDAQUILINE FUMARATE

Official Name

English

3-QUINOLINEETHANOL, 6-BROMO-.ALPHA.-(2-(DIMETHYLAMINO)ETHYL)-2-METHOXY-.ALPHA.-1-NAPHTHALENYL-.BETA.-PHENYL-, (.ALPHA.S,.BETA.R)-, (2E)-2-BUTENEDIOATE (1:1) (SALT)

Common Name

English

R-403323

Code

English

BEDAQUILINE FUMARATE [USAN]

Common Name

English

BEDAQUILINE FUMARATE [MI]

Common Name

English

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Classification Tree

Code System

Code

Antibacterial Agent

NCI_THESAURUS

C280

Positive

EU-Orphan Drug

EU/3/05/314

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Code System

Code

Type

Description

USAN

XX-136

PRIMARY

SMS_ID

100000141480

PRIMARY

DRUG BANK

DBSALT000016

PRIMARY

PUBCHEM

24812732

PRIMARY

EVMPD

SUB91883

PRIMARY

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BEDAQUILINE

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SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator