PRETOMANID

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C14H12F3N3O5
Molecular Weight	359.2574
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

[O-][N+](=O)C1=CN2C[C@@H](COC2=N1)OCC3=CC=C(OC(F)(F)F)C=C3

InChI

InChIKey=ZLHZLMOSPGACSZ-NSHDSACASA-N

InChI=1S/C14H12F3N3O5/c15-14(16,17)25-10-3-1-9(2-4-10)7-23-11-5-19-6-12(20(21)22)18-13(19)24-8-11/h1-4,6,11H,5,7-8H2/t11-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C14H12F3N3O5
Molecular Weight	359.2574
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Pretomanid (PA-824) is an experimental anti-tuberculosis drug. Pretomanid is a bicyclic nitroimidazole-like molecule with a very complex mechanism of action. It is active against both replicating and hypoxic, non-replicating Mycobacterium tuberculosis. As a potential TB therapy, it has many attractive characteristics - most notably its novel mechanism of action, its activity in vitro against all tested drug-resistant clinical isolates, and its activity as both a potent bactericidal and a sterilizing agent in mice. In addition, the compound shows no evidence of mutagenicity in a standard battery of genotoxicity studies, no significant cytochrome P450 interactions, and no significant activity against a broad range of Gram-positive and Gram-negative bacteria. This compound has been developed by TB Alliance and is a potential cornerstone of future TB and drug-resistant TB treatment regimens. It is currently undergoing Phase III clinical trials.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Mycobacterium tuberculosis H37Rv 11	Inhibitor 8,297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pulmonary tuberculosis 17	Curative		Phase III 656	Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
2 μg/mL	200 mg single, oral		PRETOMANID plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
53 μg × h/mL	200 mg single, oral		PRETOMANID plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
17.4 h	200 mg single, oral		PRETOMANID plasma	Homo sapiens

Doses

Doses

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Dose	Population	Adverse events
1200 mg 1 times / day steady, oral	unhealthy, 27 years (range:18 - 56 years)
1500 mg single, oral Highest studied dose	healthy

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781 substrate 1,737	inhibitor 1,767 inducer 389 substrate 1,037	inhibitor 1,852 substrate 1,217	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A4/5 278 CYP1A2 1,524 CYP2C8 911 CYP2C19 1,478 OAT3 642 MATE2 263 OAT1 599 OCT1 512 OCT2 647 OATP1B1 788 OATP1B3 706 BCRP 699 BSEP 402 P-gp 1,461 MATE1 306	CYP3A 191 CYP2C19 991 OAT1 326 OAT3 339 OCT2 355 OATP1B1 406 OATP1B3 350 MATE1 135 MATE2 96 BCRP 561 P-gp 1,537	CYP2E1 128

Drug as perpetrator

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Target	Modality	Activity
CYP2E1 970	inducer 1,573	inconclusive
MATE2 263	inhibitor 3,277	no [IC50 45.1 uM]
MATE1 308	inhibitor 3,277	no [IC50 87.7 uM]
CYP1A2 1,692	inhibitor 3,277	no [Inhibition 100 uM]
CYP2C9 1,819	inhibitor 3,277	no [Inhibition 100 uM]

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Drug as victim

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Target	Modality	Activity
BCRP 561	substrate 3,367	no
CYP2C19 991	substrate 3,367	no
CYP2C9 1,037	substrate 3,367	no
CYP2D6 1,217	substrate 3,367	no
MATE1 135	substrate 3,367	no

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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
AA Blocks	AA0074TR	https://www.aablocks.com/goods/Goods/detail?id=AA0074TR
Aaron Chemicals	AR0075LJ	http://www.aaronchem.com/187235-37-6
abcr GmbH	AB442440	http://www.abcr.com/shop/en/AB442440
AbMole Bioscience	M2163	http://www.abmole.com/products/pa-824.html
Aceschem	ACF023627	https://www.aceschem.com/catalog/187235-37-6.html

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PubMed

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Title	Date	PubMed
Structure-activity relationships of antitubercular nitroimidazoles. 3. Exploration of the linker and lipophilic tail of ((s)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)-(4-trifluoromethoxybenzyl)amine (6-amino PA-824).	2011 Aug 25	21755942
Chlorinated coumarins from the polypore mushroom Fomitopsis officinalis and their activity against Mycobacterium tuberculosis.	2013 Oct 25	24087924
Pentacyclic nitrofurans with in vivo efficacy and activity against nonreplicating Mycobacterium tuberculosis.	2014	24505329

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Patents

Sample Use Guides

In Vivo Use Guide

oral administration of Pretomanid (PA-824) at 200, 600, 1000 and 1200 mg per day

Route of Administration: Oral

In Vitro Use Guide

Minimum bactericidal concentration against Mycobacterium tuberculosis was 6.4-12.8 ug/mL

Substance Class	Chemical
Record UNII	2XOI31YC4N
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

PRETOMANID

Official Name

English

(S)-2-NITRO-6-(4-(TRIFLUOROMETHOXY)BENZYLOXY)-6,7-DIHYDRO-5H-IMIDAZO(2,1-B)(1,3)OXAZINE

Systematic Name

English

PA-824

Code

English

Pretomanid [WHO-DD]

Common Name

English

pretomanid [INN]

Common Name

English

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Classification Tree

Code System

Code

Positive

EU-Orphan Drug

EU/3/07/513

Designated/Approved

FDA ORPHAN DRUG

243107

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Code System

Code

Type

Description

DRUG BANK

DB05154

PRIMARY

DAILYMED

2XOI31YC4N

PRIMARY

DRUG CENTRAL

5344

PRIMARY

WIKIPEDIA

Pretomanid

PRIMARY

CAS

187235-37-6

PRIMARY

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Related Record

Type

Details


					ZWJ2Y6JZWY

OAT-3

TRANSPORTER -> INHIBITOR

Comments:

In vitro studies indicate that pretomanid significantly inhibits the OAT3 drug transporter which could result in increased concentrations of OAT3 substrates at clinically relevant concentrations of pretomanid. No clinical DDI studies have been conducted with OAT3 substrates.


					L0423Z5LDW

CYTOCHROME P450 2C8

METABOLIC ENZYME -> INHIBITOR

Comments:

Pretomanid is a weak time-dependent inhibitor of CYP2C8 and CYP2C19.

Interaction Type:

TIME-DEPENDENT INHIBITION


					081I12ZA58

CYTOCHROME P450 2C19

METABOLIC ENZYME -> INHIBITOR

Comments:

Pretomanid is a weak time-dependent inhibitor of CYP2C8 and CYP2C19.

Interaction Type:

TIME-DEPENDENT INHIBITION


					R0EM8D5HFD

MYCOBACTERIUM TUBERCULOSIS

TARGET ORGANISM->INHIBITOR


					2XOI31YC4N

PRETOMANID

EXCRETED UNCHANGED

Interaction Type:

AMOUNT EXCRETED

Qualification:

FECAL; URINE

Amount:

[<5] % (average)

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Related Record

Type

Details


					C658O375NL

2-HYDROXYIMIDAZOLE

METABOLITE -> PARENT

Qualification:

PLASMA

Amount:

6.3 % (average)
of radioactivity


					KPJ4EW9JVT

2-AMINO-1,3-OXAZINAN-5-OL

METABOLITE -> PARENT

Qualification:

PLASMA

Amount:

5.1 % (average)
of radioactivity

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Related Record

Type

Details


					2XOI31YC4N

PRETOMANID

ACTIVE MOIETY

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Name	Property Type	Amount	Parameters
Tmax	PHYSICAL	4 hours [2 to 6] (average)	FASTED CONDITION SINGLE DOSE ADMINISTRATION 200 mg (average)

Biological Half-life	PHARMACOKINETIC	16.9 hours (average)	FASTED CONDITION SINGLE DOSE ADMINISTRATION 200 mg (average)

Tmax	PHARMACOKINETIC	5 hours [3 to 8.1] (average)	SINGLE DOSE ADMINISTRATION 200 mg (average) FED CONDITION

Volume of Distribution	PHARMACOKINETIC	97 LITERS (average)	SINGLE DOSE ADMINISTRATION FED CONDITION

Volume of Distribution	PHARMACOKINETIC	180 LITERS (average)	FASTED CONDITION SINGLE DOSE ADMINISTRATION 200 mg (average)

Biological Half-life	PHARMACOKINETIC	17.4 hours (average)	FED CONDITION SINGLE DOSE ADMINISTRATION 200 mg (average)

SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Doses

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

Drug as perpetrator