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Details

Stereochemistry ABSOLUTE
Molecular Formula C14H12F3N3O5
Molecular Weight 359.2579
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of PRETOMANID

SMILES

c1cc(ccc1CO[C@@]2([H])Cn3cc(nc3OC2)N(=O)=O)OC(F)(F)F

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 359.2579
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
Curator's Comment:: http://adisinsight.springer.com/drugs/800007841

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

Curator's Comment:: # Novartis

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Conditions

Conditions

Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
2 μg/mL
200 mg single, oral
dose: 200 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
PRETOMANID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: FED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
53 μg × h/mL
200 mg single, oral
dose: 200 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
PRETOMANID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: FED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
17.4 h
200 mg single, oral
dose: 200 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
PRETOMANID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: FED
Doses

Doses

DosePopulationAdverse events​
1200 mg 1 times / day steady, oral
Dose: 1200 mg, 1 times / day
Route: oral
Route: steady
Dose: 1200 mg, 1 times / day
Sources:
unhealthy, 27 years (range:18 - 56 years)
Health Status: unhealthy
Age Group: 27 years (range:18 - 56 years)
Sex: M+F
Sources:
1500 mg single, oral
Highest studied dose
Dose: 1500 mg
Route: oral
Route: single
Dose: 1500 mg
Sources:
healthy
Health Status: healthy
Sex: M
Sources:
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
inconclusive
no [IC50 45.1 uM]
no [IC50 87.7 uM]
no [Inhibition 100 uM]
no [Inhibition 100 uM]
no [Inhibition 100 uM]
no
no
no
no
no
no
no
no
no
no
weak (co-administration study)
Comment: resulted in a decrease in midazolam mean AUC by 15% and Cmax by 16 % and an increase in 1-hydroxy midazolam mean AUC by 14 % and Cmax by 5%.
Page: 71
unlikely [IC50 13 uM]
weak (co-administration study)
Comment: IC value is from time-dependent inhibition; when midazolam is co-administered: resulted in a decrease in midazolam mean AUC by 15% and Cmax by 16 % and an increase in 1-hydroxy midazolam mean AUC by 14 % and Cmax by 5%.
Page: 71;75;76;297
weak [IC50 30 uM]
unlikely
Comment: IC value is from time dependent inhibition;
Page: 71;76;297
weak [IC50 48 uM]
unlikely
Comment: IC value is from time dependent inhibition;
Page: 71;76;297
yes
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
no
no
no
no
no
no
no
no
no
no
no
no
yes
weak (co-administration study)
Comment: Co-administration with lopinavir/ritonavir resulted in a decrease of pretomanid mean AUC by 17% and Cmax by 13%. Mean AUC and Cmax of lopinavir was decreased by 14 % and 17 %, respectively.
Page: 71,75
yes
yes (co-administration study)
Comment: CYP3A4 accounts for up to approximately 20% of the metabolism of pretomanid; Co-administration of retomanid (inducer) resulted in a decrease of pretomanid mean AUC by 66% and Cmax by 53%; Co-administration of pretomanid with efavirenz resulted in a decrease of pretomanid mean AUC by 35% and Cmax by 28%. Mean AUC and Cmax of efavirenz was decreased by 4 % and 14 %, respectively.
Page: 71,75
Tox targets

Tox targets

PubMed

PubMed

TitleDatePubMed
A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis.
2000 Jun 22
Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models.
2005 Jun
Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis.
2005 Jun
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a murine model of tuberculosis.
2006 Aug
Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis.
2006 Jan 10
A microbiological assessment of novel nitrofuranylamides as anti-tuberculosis agents.
2008 Nov
Discovery and development of the covalent hydrates of trifluoromethylated pyrazoles as riboflavin synthase inhibitors with antibiotic activity against Mycobacterium tuberculosis.
2009 Aug 7
Synthesis, reduction potentials, and antitubercular activity of ring A/B analogues of the bioreductive drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824).
2009 Feb 12
Structure-activity relationships of antitubercular nitroimidazoles. 2. Determinants of aerobic activity and quantitative structure-activity relationships.
2009 Mar 12
Structure-activity relationships of antitubercular nitroimidazoles. 1. Structural features associated with aerobic and anaerobic activities of 4- and 5-nitroimidazoles.
2009 Mar 12
Synthesis, antimalarial and antitubercular activity of acetylenic chalcones.
2010 Feb 1
Synthesis and structure-activity studies of biphenyl analogues of the tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824).
2010 Jan 14
Rational design of 5-phenyl-3-isoxazolecarboxylic acid ethyl esters as growth inhibitors of Mycobacterium tuberculosis. a potent and selective series for further drug development.
2010 Jan 28
Synthesis and structure-activity relationships of antitubercular 2-nitroimidazooxazines bearing heterocyclic side chains.
2010 Jan 28
Synthesis of non-purine analogs of 6-aryl-9-benzylpurines, and their antimycobacterial activities. Compounds modified in the imidazole ring.
2010 Oct 15
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
Chlorinated coumarins from the polypore mushroom Fomitopsis officinalis and their activity against Mycobacterium tuberculosis.
2013 Oct 25
Pentacyclic nitrofurans with in vivo efficacy and activity against nonreplicating Mycobacterium tuberculosis.
2014
Patents

Sample Use Guides

oral administration of Pretomanid (PA-824) at 200, 600, 1000 and 1200 mg per day
Route of Administration: Oral
Minimum bactericidal concentration against Mycobacterium tuberculosis was 6.4-12.8 ug/mL
Substance Class Chemical
Created
by admin
on Fri Jun 25 22:44:15 UTC 2021
Edited
by admin
on Fri Jun 25 22:44:15 UTC 2021
Record UNII
2XOI31YC4N
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
PRETOMANID
INN   USAN   WHO-DD  
INN   USAN  
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 [INN]
Common Name English
PA 824
Code English
PRETOMANID [ORANGE BOOK]
Common Name English
(3S)-3-(4-TRIFLUOROMETHOXYBENZYLOXY)-6-NITRO-2H-3,4-DIHYDROIMIDAZO(2,1-B)OXAZINE
Common Name English
PRETOMANID [MI]
Common Name English
PRETOMANID [WHO-DD]
Common Name English
PRETOMANID [USAN]
Common Name English
PA824
Code English
Classification Tree Code System Code
EU-Orphan Drug EU/3/07/513
Created by admin on Fri Jun 25 22:44:15 UTC 2021 , Edited by admin on Fri Jun 25 22:44:15 UTC 2021
FDA ORPHAN DRUG 243107
Created by admin on Fri Jun 25 22:44:15 UTC 2021 , Edited by admin on Fri Jun 25 22:44:15 UTC 2021
Code System Code Type Description
DRUG BANK
DB05154
Created by admin on Fri Jun 25 22:44:15 UTC 2021 , Edited by admin on Fri Jun 25 22:44:15 UTC 2021
PRIMARY
DRUG CENTRAL
5344
Created by admin on Fri Jun 25 22:44:15 UTC 2021 , Edited by admin on Fri Jun 25 22:44:15 UTC 2021
PRIMARY
CAS
187235-37-6
Created by admin on Fri Jun 25 22:44:15 UTC 2021 , Edited by admin on Fri Jun 25 22:44:15 UTC 2021
PRIMARY
EPA CompTox
187235-37-6
Created by admin on Fri Jun 25 22:44:15 UTC 2021 , Edited by admin on Fri Jun 25 22:44:15 UTC 2021
PRIMARY
ChEMBL
CHEMBL227875
Created by admin on Fri Jun 25 22:44:15 UTC 2021 , Edited by admin on Fri Jun 25 22:44:15 UTC 2021
PRIMARY
MERCK INDEX
M12157
Created by admin on Fri Jun 25 22:44:15 UTC 2021 , Edited by admin on Fri Jun 25 22:44:15 UTC 2021
PRIMARY
FDA UNII
2XOI31YC4N
Created by admin on Fri Jun 25 22:44:15 UTC 2021 , Edited by admin on Fri Jun 25 22:44:15 UTC 2021
PRIMARY
INN
9871
Created by admin on Fri Jun 25 22:44:15 UTC 2021 , Edited by admin on Fri Jun 25 22:44:15 UTC 2021
PRIMARY
PUBCHEM
456199
Created by admin on Fri Jun 25 22:44:15 UTC 2021 , Edited by admin on Fri Jun 25 22:44:15 UTC 2021
PRIMARY
LACTMED
Pretomanid
Created by admin on Fri Jun 25 22:44:15 UTC 2021 , Edited by admin on Fri Jun 25 22:44:15 UTC 2021
PRIMARY
RXCUI
2198359
Created by admin on Fri Jun 25 22:44:15 UTC 2021 , Edited by admin on Fri Jun 25 22:44:15 UTC 2021
PRIMARY
NCI_THESAURUS
C166606
Created by admin on Fri Jun 25 22:44:15 UTC 2021 , Edited by admin on Fri Jun 25 22:44:15 UTC 2021
PRIMARY
EVMPD
SUB96086
Created by admin on Fri Jun 25 22:44:15 UTC 2021 , Edited by admin on Fri Jun 25 22:44:15 UTC 2021
PRIMARY
Related Record Type Details
TRANSPORTER -> INHIBITOR
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.
METABOLIC ENZYME -> INHIBITOR
Pretomanid is a weak time-dependent inhibitor of CYP2C8 and CYP2C19.
TIME-DEPENDENT INHIBITION
METABOLIC ENZYME -> INHIBITOR
Pretomanid is a weak time-dependent inhibitor of CYP2C8 and CYP2C19.
TIME-DEPENDENT INHIBITION
TARGET ORGANISM->INHIBITOR
EXCRETED UNCHANGED
AMOUNT EXCRETED
FECAL; URINE
METABOLIC ENZYME -> SUBSTRATE
MAJOR
BINDER->LIGAND
Human plasma protein binding of pretomanid is approximately 86.4% and is independent of drug concentration.
BINDING
Related Record Type Details
METABOLITE -> PARENT
PLASMA
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Tmax PHYSICAL FASTED CONDITION

SINGLE DOSE ADMINISTRATION

Biological Half-life PHARMACOKINETIC FASTED CONDITION

SINGLE DOSE ADMINISTRATION

Tmax PHARMACOKINETIC SINGLE DOSE ADMINISTRATION

FED CONDITION

Volume of Distribution PHARMACOKINETIC SINGLE DOSE ADMINISTRATION

FED CONDITION

Volume of Distribution PHARMACOKINETIC FASTED CONDITION

SINGLE DOSE ADMINISTRATION

Biological Half-life PHARMACOKINETIC FED CONDITION

SINGLE DOSE ADMINISTRATION