Details of the Drug

General Information of Drug (ID: DMDYA31)

Drug Name

Pretomanid

Synonyms

PA-824; 187235-37-6; Pretomanid; PA 824; PA824; UNII-2XOI31YC4N; (S)-PA 824; (S)-2-Nitro-6-((4-(trifluoromethoxy)benzyl)oxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine; 2XOI31YC4N; CHEMBL227875; MMV688755; AK161427; (6S)-2-nitro-6-[[4-(trifluoromethoxy)phenyl]methoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine; (6S)-6,7-Dihydro-2-nitro-6-[[4-(trifluoromethoxy)phenyl]methoxy]-5H-imidazo[2,1-b][1,3]oxazine; Pretomanid [USAN:INN]; C14H12F3N3O5; PA-824(Pretomanid); AC1L9UFX; Pretomanid (USAN/INN); MLS006011141; SCHEMBL2983011

Indication

Disease Entry	ICD 11	Status	REF
Tuberculosis	1B10-1B14	Approved	[1]
Mycobacterium infection	1B10-1B21	Phase 3	[2]
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Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 0

Molecular Weight (mw)

359.26

Logarithm of the Partition Coefficient (xlogp)

2.8

Rotatable Bond Count (rotbonds)

4

Hydrogen Bond Donor Count (hbonddonor)

0

Hydrogen Bond Acceptor Count (hbondacc)

9

ADMET Property

Absorption AUC: The area under the plot of plasma concentration (AUC) of drug is 28.1 mgh/L [3]
Absorption Cmax: The maximum plasma concentration (Cmax) of drug is 1.7 mg/L [3]
Absorption Tmax: The time to maximum plasma concentration (Tmax) is 4-5 h [3]
Clearance: The clearance of drug is 4.8 +/- 0.2 L/h [4]
Elimination: An average of about 53% of the radioactive dose was found to be excreted in the urine [3]
Half-life: The concentration or amount of drug in body reduced by one-half in 16.9 - 17.4 hours [3]
Vd: The volume of distribution (Vd) of drug is 130 +/- 5 L [4]

Chemical Identifiers

Formula: C14H12F3N3O5
IUPAC Name: (6S)-2-nitro-6-[[4-(trifluoromethoxy)phenyl]methoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
Canonical SMILES: C1[C@@H](COC2=NC(=CN21)[N+](=O)[O-])OCC3=CC=C(C=C3)OC(F)(F)F
InChI: 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
InChIKey: ZLHZLMOSPGACSZ-NSHDSACASA-N

Cross-matching ID

PubChem CID: 456199
CAS Number: 187235-37-6
DrugBank ID: DB05154
TTD ID: D02AYL
INTEDE ID: DR1338
ACDINA ID: D01360

Combinatorial Drugs (CBD)

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Repurposed Drugs (RPD)

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Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Mycobacterium Mycolic acid synthase (MycB cma)	TT08ESN	CMAS1_MYCTU ; CMAS2_MYCTU ; CMAS3_MYCTU	Inhibitor	[1]

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Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)_{Main DME}	DE4LYSA	CP3A4_HUMAN	Substrate	[5]

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Molecular Interaction Atlas (MIA)

MIA Detail

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Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Pretomanid (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Arn-509	DMT81LZ	Major	Increased metabolism of Pretomanid caused by Arn-509 mediated induction of CYP450 enzyme.	Acute myeloid leukaemia [2A60]	[6]
Pexidartinib	DMS2J0Z	Major	Increased metabolism of Pretomanid caused by Pexidartinib mediated induction of CYP450 enzyme.	Bone/articular cartilage neoplasm [2F7B]	[6]
Lumacaftor	DMCLWDJ	Major	Increased metabolism of Pretomanid caused by Lumacaftor mediated induction of CYP450 enzyme.	Cystic fibrosis [CA25]	[7]
Cenobamate	DM8KLU9	Major	Increased metabolism of Pretomanid caused by Cenobamate mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[6]
Eslicarbazepine	DMZREFQ	Major	Increased metabolism of Pretomanid caused by Eslicarbazepine mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[6]
Etravirine	DMGV8QU	Major	Increased metabolism of Pretomanid caused by Etravirine mediated induction of CYP450 enzyme.	Human immunodeficiency virus disease [1C60-1C62]	[6]
PF-06463922	DMKM7EW	Major	Increased metabolism of Pretomanid caused by PF-06463922 mediated induction of CYP450 enzyme.	Lung cancer [2C25]	[6]
Dabrafenib	DMX6OE3	Major	Increased metabolism of Pretomanid caused by Dabrafenib mediated induction of CYP450 enzyme.	Melanoma [2C30]	[6]
Abametapir	DM2RX0I	Moderate	Decreased metabolism of Pretomanid caused by Abametapir mediated inhibition of CYP450 enzyme.	Pediculosis [1G00]	[8]
Lefamulin	DME6G97	Moderate	Decreased metabolism of Pretomanid caused by Lefamulin mediated inhibition of CYP450 enzyme.	Pneumonia [CA40]	[9]
Enzalutamide	DMGL19D	Major	Increased metabolism of Pretomanid caused by Enzalutamide mediated induction of CYP450 enzyme.	Prostate cancer [2C82]	[6]
Telotristat ethyl	DMDIYFZ	Major	Increased metabolism of Pretomanid caused by Telotristat ethyl mediated induction of CYP450 enzyme.	Small intestine developmental anomaly [DA90]	[7]
Pitolisant	DM8RFNJ	Major	Increased metabolism of Pretomanid caused by Pitolisant mediated induction of CYP450 enzyme.	Somnolence [MG42]	[6]
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Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Sodium lauryl sulfate	E00464	3423265	Emulsifying agent; Modified-release agent; Penetration agent; Solubilizing agent; Surfactant; lubricant
Lactose monohydrate	E00393	104938	Binding agent; Diluent; Dry powder inhaler carrier; Lyophilization aid
Magnesium stearate	E00208	11177	lubricant
Povidone	E00667	Not Available	Binding agent; Coating agent; Disintegrant; Film/membrane-forming agent; Solubilizing agent; Suspending agent
Hydrophobic colloidal silica	E00285	24261	Anticaking agent; Emulsion stabilizing agent; Glidant; Suspending agent; Viscosity-controlling agent
Cellulose microcrystalline	E00698	Not Available	Adsorbent; Suspending agent; Diluent
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Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Pretomanid 200 mg tablet	200 mg	Tablet	Oral

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References

1	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
2	ClinicalTrials.gov (NCT02342886) Shortening Treatment by Advancing Novel Drugs. U.S. National Institutes of Health.
3	Pretomanid FDA label, August 2019
4	Lyons MA: Modeling and Simulation of Pretomanid Pharmacokinetics in Pulmonary Tuberculosis Patients. Antimicrob Agents Chemother. 2018 Jun 26;62(7). pii: AAC.02359-17. doi: 10.1128/AAC.02359-17. Print 2018 Jul.
5	FDA briefing document - pretomanid tablet, 200 mg meeting of the antimicrobial drugs advisory committee (AMDAC).
6	Product Information. Pretomanid (pretomanid). The Global Alliance for TB Drug Development, New York, NY.
7	Patel S, Robinson R, Burk M "Hypertensive crisis associated with St. John's Wort." Am J Med 112 (2002): 507-8. [PMID: 11959071]
8	Product Information. Xeglyze (abametapir topical). Dr. Reddy's Laboratories Inc, Upper Saddle River, NJ.
9	Product Information. Fycompa (perampanel). Eisai Inc, Teaneck, NJ.