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 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pulmonary tuberculosis 17 Sources: http://adisinsight.springer.com/drugs/800007841	Curative		Phase III 656	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) n = 15 Health Status: unhealthy Age Group: 27 years (range:18 - 56 years) Sex: M+F Population Size: 15 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 n = 8 Health Status: healthy Sex: M Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/31358590	Sources: https://pubmed.ncbi.nlm.nih.gov/31358590

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781 substrate 1737	inhibitor 1767 inducer 389 substrate 1037	inhibitor 1852 substrate 1217	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A4/5 278 CYP1A2 1524 CYP2C8 911 CYP2C19 1478 OAT3 642 MATE2 263 OAT1 599 OCT1 512 OCT2 647 OATP1B1 788 OATP1B3 706 BCRP 699 BSEP 402 P-gp 1461 MATE1 306	CYP3A 191 CYP2C19 991 OAT1 326 OAT3 339 OCT2 355 OATP1B1 406 OATP1B3 350 MATE1 135 MATE2 96 BCRP 561 P-gp 1537	CYP2E1 128

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP2E1 970	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=303 Page: 303.0	inconclusive
MATE2 263	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71;294	no [IC50 45.1 uM]
MATE1 308	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71294.0	no [IC50 87.7 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71;76;297	no [Inhibition 100 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71;76;297	no [Inhibition 100 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71;76;297	no [Inhibition 100 uM]
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
BSEP 403	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OCT1 543	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
CYP3A4 1925	inducer 1573 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
CYP3A4/5 335	inhibitor 3277 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 965	inhibitor 3277 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 1553	inhibitor 3277 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 644	inhibitor 3277 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 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
MATE1 135	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
MATE2 96	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OAT1 326	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OAT3 339	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OATP1B1 406	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OATP1B3 350	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
OCT2 355	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212862Orig1s000MultidisciplineR.pdf#page=71 Page: 71.0	no
CYP3A 191	substrate 3367 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 1737	substrate 3367 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 1647	inhibitor 1626 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
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
Aaron Chemicals	AR0075LJ	http://www.aaronchem.com/187235-37-6
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	PA-824	http://www.adooq.com/pa-824.html
Adooq BioScience	A11401	https://www.adooq.com/pa-824.html
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
CSNpharm	CSN13811	https://www.csnpharm.com/products/pa-824.html
Chem Scene	CS-3090	http://www.chemscene.com/187235-37-6.html
Chemspace	CSSB00016993066	https://chem-space.com/CSSB00016993066
DC Chemicals	DC7625	http://www.dcchemicals.com/product_show-PA_824_Pretomanid_.html
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
abcr GmbH	AB442440	http://www.abcr.com/shop/en/AB442440
eNovation Chemicals	D408823	http://www.enovationchem.com/productDetails.asp?productID=D408823
eNovation Chemicals	Y0974056	https://www.enovationchem.com/ProductDetails.asp?ProductID=Y0974056

PubMed

Title	Date	PubMed
A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis.	2000 Jun 22	10879539
Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models.	2005 Jun	15917524
Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis.	2005 Jun	15917523
Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a murine model of tuberculosis.	2006 Aug	16870750
Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis.	2006 Jan 10	16387854
A microbiological assessment of novel nitrofuranylamides as anti-tuberculosis agents.	2008 Nov	18693235
Discovery and development of the covalent hydrates of trifluoromethylated pyrazoles as riboflavin synthase inhibitors with antibiotic activity against Mycobacterium tuberculosis.	2009 Aug 7	19545132
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	19099398
Structure-activity relationships of antitubercular nitroimidazoles. 2. Determinants of aerobic activity and quantitative structure-activity relationships.	2009 Mar 12	19209893
Structure-activity relationships of antitubercular nitroimidazoles. 1. Structural features associated with aerobic and anaerobic activities of 4- and 5-nitroimidazoles.	2009 Mar 12	19209889
Synthesis, antimalarial and antitubercular activity of acetylenic chalcones.	2010 Feb 1	20045640
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	19928920
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	20000577
Synthesis and structure-activity relationships of antitubercular 2-nitroimidazooxazines bearing heterocyclic side chains.	2010 Jan 28	19968290
Synthesis of non-purine analogs of 6-aryl-9-benzylpurines, and their antimycobacterial activities. Compounds modified in the imidazole ring.	2010 Oct 15	20833056
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

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

(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

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