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

Structure Search

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

Description
Sources: https://www.tballiance.org/portfolio/compound/pretomanid
Curator's Comment: Description was created based on several sources, including 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

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Mycobacterium tuberculosis H37Rv 11 Target ID: CHEMBL2111188 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26199118	Inhibitor 8504

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pulmonary tuberculosis 17 Sources: http://adisinsight.springer.com/drugs/800007841	Curative		Phase III 665	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
2 μg/mL EXPERIMENT https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000Lbl.pdf	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

Value	Dose	Co-administered	Analyte	Population
53 μg × h/mL EXPERIMENT https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000Lbl.pdf	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

T_1/2

Value	Dose	Co-administered	Analyte	Population
17.4 h EXPERIMENT https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000Lbl.pdf	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

Dose	Population	Adverse 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: https://pubmed.ncbi.nlm.nih.gov/31570404	unhealthy, 27 years (range:18 - 56 years) Health Status: unhealthy Age Group: 27 years (range:18 - 56 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/31570404	Sources: https://pubmed.ncbi.nlm.nih.gov/31570404
1500 mg single, oral Highest studied dose Dose: 1500 mg Route: oral Route: single Dose: 1500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/31358590	healthy Health Status: healthy Sex: M Sources: https://pubmed.ncbi.nlm.nih.gov/31358590	Sources: https://pubmed.ncbi.nlm.nih.gov/31358590

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 1087 substrate 1946	inhibitor 2438 inducer 440 substrate 1193	inhibitor 2507 substrate 1388	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A4/5 296 CYP1A2 2153 CYP2C8 1057 CYP2C19 2057 OAT3 747 MATE2 267 OAT1 725 OCT1 620 OCT2 779 OATP1B1 1079 OATP1B3 961 BCRP 910 BSEP 550 P-gp 1741 MATE1 415	CYP3A 220 CYP2C19 1119 OAT1 395 OAT3 391 OCT2 434 OATP1B1 503 OATP1B3 435 MATE1 182 MATE2 98 BCRP 697 P-gp 2052	CYP2E1 131

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP2E1 1146	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=303 Page: 303.0	inconclusive
MATE2 267	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71;294	no [IC50 45.1 uM]
MATE1 416	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71294.0	no [IC50 87.7 uM]
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71;76;297	no [Inhibition 100 uM]
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71;76;297	no [Inhibition 100 uM]
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71;76;297	no [Inhibition 100 uM]
BCRP 985	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
BSEP 554	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
CYP2C9 2497	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OAT1 730	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OATP1B1 1095	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OATP1B3 970	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OCT1 656	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OCT2 782	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
P-gp 1932	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
CYP3A4 2633	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	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%. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0
CYP3A4/5 357	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71;75;76;297	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%. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71;75;76;297
CYP2C8 1117	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71;76;297	weak [IC50 30 uM]	unlikely Comment: IC value is from time dependent inhibition; Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71;76;297
CYP2C19 2141	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71;76;297	weak [IC50 48 uM]	unlikely Comment: IC value is from time dependent inhibition; Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71;76;297
OAT3 749	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71;76	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
BCRP 697	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
CYP2C19 1119	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
CYP2C9 1193	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
CYP2D6 1388	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
MATE1 182	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
MATE2 98	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OAT1 395	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OAT3 391	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OATP1B1 503	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OATP1B3 435	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OCT2 434	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
P-gp 2052	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
CYP3A 220	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71,75	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. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71,75
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 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. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71,75

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=40 Page: 43.0

Sourcing

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
Achemtek	0102-011680	http://www.achemtek.com/187235-37-6
Acorn PharmaTech	ACN-052207	http://www.acornpharmatech.com/
Adooq BioScience	A11401	https://www.adooq.com/pa-824.html
Adooq BioScience	PA-824	http://www.adooq.com/pa-824.html
AEchem Scientific Corp., USA	AE052288	http://www.aechemsc.com/info_products/AE052288.php
AK Scientific, Inc. (AKSCI)	X6951	http://www.aksci.com/item_detail.php?cat=X6951
Alfa Chemistry	AP187235376	https://reagents.alfa-chemistry.com/product/pa-824-cas-187235-37-6-6960.html
Alsachim	4570	http://www.alsachim.com/product-C5916-glo.bal-view.html
Ambinter	Amb22738579	http://www.ambinter.com/reference/22738579
Angene	AGN-PC-0QGDB3	http://www.angenechemical.com/productshow/AGN-PC-0QGDB3.html
ApexBio Technology	A1736	http://www.apexbt.com/pa-824.html
Aurora Fine Chemicals LLC	A17.869.878	http://online.aurorafinechemicals.com/info?ID=A17.869.878
BioCrick	BCC1106	http://www.biocrick.com/PA-824-BCC1106.html
Chem Scene	CS-3090	http://www.chemscene.com/187235-37-6.html
Chemspace	CSSB00016993066	https://chem-space.com/CSSB00016993066
CSNpharm	CSN13811	https://www.csnpharm.com/products/pa-824.html
DC Chemicals	DC7625	http://www.dcchemicals.com/product_show-PA_824_Pretomanid_.html
eNovation Chemicals	D408823	http://www.enovationchem.com/productDetails.asp?productID=D408823
eNovation Chemicals	Y0974056	https://www.enovationchem.com/ProductDetails.asp?ProductID=Y0974056
Excenen	EX-A1749	http://www.excenen.com/searchresultlist.php?id=187235-37-6
Hairui	PRCQ002	http://www.hairuichem.com/en/product/187235-37-6.html
Lab Network	LN00218318	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN00218318
Matrix Scientific	118158	https://www.matrixscientific.com/118158.html
MedChem Express	HY-10844	https://www.medchemexpress.com/PA-824.html
Selleck Chemicals	S1162	http://www.selleckchem.com/products/pa-824.html
Smolecule	S540167	http://www.smolecule.com/products/s540167
Synblock Inc	SB22927	http://www.synblock.com/product/187235-37-6.html
THE BioTek	bt-279879	https://www.thebiotek.com/product/inhibitors/bt-279879

PubMed

Title	Date	PubMed
Pentacyclic nitrofurans with in vivo efficacy and activity against nonreplicating Mycobacterium tuberculosis.	2014	24505329
Chlorinated coumarins from the polypore mushroom Fomitopsis officinalis and their activity against Mycobacterium tuberculosis.	2013-10-25	24087924
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).	2011-08-25	21755942
Synthesis of non-purine analogs of 6-aryl-9-benzylpurines, and their antimycobacterial activities. Compounds modified in the imidazole ring.	2010-10-15	20833056
Synthesis, antimalarial and antitubercular activity of acetylenic chalcones.	2010-02-01	20045640
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.	2010-01-28	20000577
Synthesis and structure-activity relationships of antitubercular 2-nitroimidazooxazines bearing heterocyclic side chains.	2010-01-28	19968290
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).	2010-01-14	19928920
Discovery and development of the covalent hydrates of trifluoromethylated pyrazoles as riboflavin synthase inhibitors with antibiotic activity against Mycobacterium tuberculosis.	2009-08-07	19545132
Structure-activity relationships of antitubercular nitroimidazoles. 2. Determinants of aerobic activity and quantitative structure-activity relationships.	2009-03-12	19209893
Structure-activity relationships of antitubercular nitroimidazoles. 1. Structural features associated with aerobic and anaerobic activities of 4- and 5-nitroimidazoles.	2009-03-12	19209889
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).	2009-02-12	19099398
A microbiological assessment of novel nitrofuranylamides as anti-tuberculosis agents.	2008-11	18693235
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a murine model of tuberculosis.	2006-08	16870750
Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis.	2006-01-10	16387854
Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models.	2005-06	15917524
Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis.	2005-06	15917523
A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis.	2000-06-22	10879539

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

Name

Type

Language

PRETOMANID

Official Name

English

pretomanid [INN]

Preferred 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

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 [USAN]

Common Name

English

PA824

Code

English

Classification Tree Code System Code

EU-Orphan Drug

EU/3/07/513