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Pretomanid

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Also known as: Pa-824, 187235-37-6, Pa 824, Pa824, (s)-2-nitro-6-((4-(trifluoromethoxy)benzyl)oxy)-6,7-dihydro-5h-imidazo[2,1-b][1,3]oxazine, (s)-pa 824

Molecular Formula

C₁₄H₁₂F₃N₃O₅

Molecular Weight

359.26 g/mol

InChI Key

ZLHZLMOSPGACSZ-NSHDSACASA-N

FDA UNII

2XOI31YC4N

Persistent forms of tuberculosis (TB) have proven to be a major cause of global morbidity and mortality and a cause for significant concern. Research in recent years has been geared toward the development of novel therapies that target persistent forms of this disease, which have shown resistance to standard therapy regimens. Pretomanid is an antimycobacterial agent that is administered with [Bedaquiline] and [Linezolid] to treat resistant forms of pulmonary TB. It was the first TB drug developed by a nonprofit organization, known as TB Alliance, and was granted FDA approval on August 14, 2019. Unlike other therapeutic regimens for the treatment of resistant TB, which may take 18 months or longer and may not be effective, the pretomanid-containing regimen allows for a more efficacious and shorter duration of treatment with fewer drugs.

1 2D Structure

Pretomanid

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

(6S)-2-nitro-6-[[4-(trifluoromethoxy)phenyl]methoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

2.1.2 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

2.1.3 InChI Key

ZLHZLMOSPGACSZ-NSHDSACASA-N

2.1.4 Canonical SMILES

C1C(COC2=NC(=CN21)[N+](=O)[O-])OCC3=CC=C(C=C3)OC(F)(F)F

2.1.5 Isomeric SMILES

C1[C@@H](COC2=NC(=CN21)[N+](=O)[O-])OCC3=CC=C(C=C3)OC(F)(F)F

2.2 Other Identifiers

2.2.1 UNII

2XOI31YC4N

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 2-nitro-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5h-imidazo(2,1-b)(1,3)oxazine

2. Pa 824

3. Pa-824

4. Pa824 Cpd

2.3.2 Depositor-Supplied Synonyms

1. Pa-824

2. 187235-37-6

3. Pa 824

4. Pa824

5. (s)-2-nitro-6-((4-(trifluoromethoxy)benzyl)oxy)-6,7-dihydro-5h-imidazo[2,1-b][1,3]oxazine

6. (s)-pa 824

7. 2xoi31yc4n

8. Chembl227875

9. Mmv688755

10. (6s)-2-nitro-6-[[4-(trifluoromethoxy)phenyl]methoxy]-6,7-dihydro-5h-imidazo[2,1-b][1,3]oxazine

11. (6s)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5h-imidazo[2,1-b][1,3]oxazine

12. (6s)-2-nitro-6-{[4-(trifluoromethoxy)phenyl]methoxy}-5h,6h,7h-imidazo[2,1-b][1,3]oxazine

13. Pretomanid [usan:inn]

14. Unii-2xoi31yc4n

15. Pretomanid (tn)

16. Pa-824(pretomanid)

17. Pretomanid [mi]

18. Pretomanid [inn]

19. Pretomanid (usan/inn)

20. Pretomanid [usan]

21. Pretomanid [who-dd]

22. Mls006011141

23. Schembl2983011

24. Dtxsid8041163

25. Pretomanid [orange Book]

26. Gtpl11172

27. Ex-a1749

28. Zinc3821675

29. Bdbm50363237

30. Cs1245

31. Mfcd06809939

32. S1162

33. Akos024464713

34. Ccg-268145

35. Db05154

36. Ds-7321

37. 2-nitro-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5h-imidazo(2,1-b)(1,3)oxazine

38. Ncgc00346682-01

39. Ncgc00346682-02

40. Ac-25501

41. Hy-10844

42. Smr004702918

43. P2718

44. Sw220281-1

45. D10722

46. A855886

47. Sr-05000022748

48. Q7118312

49. Sr-05000022748-1

50. (3s)-3-(4-trifluoromethoxybenzyloxy)-6-nitro-2h-3,4-dihydroimidazo(2,1-b)oxazine

51. (s)-2-nitro-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5h-imidazo(2,1-b)(1,3)oxazine

52. {4-[((3s)-6-nitro(2h,3h,4h-imidazolo[2,1-b]1,3-oxazaperhydroin-3-yloxy))methyl]phenoxy}trifluoromethane

53. 5h-imidazo(2,1-b)(1,3)oxazine, 6,7-dihydro-2-nitro-6-((4-(trifluoromethoxy)phenyl)methoxy)-, (6s)-

54. Pretomanid;(6s)-6,7-dihydro-2-nitro-6-[[4-(trifluoromethoxy)phenyl]methoxy]-5h-imidazo[2,1-b][1,3]oxazine

2.4 Create Date

2005-08-01

3 Chemical and Physical Properties

Molecular Formula	C₁₄H₁₂F₃N₃O₅
Molecular Weight	359.26 g/mol
XLogP3	2.8
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	4
Exact Mass	359.07290498 g/mol
Monoisotopic Mass	359.07290498 g/mol
Topological Polar Surface Area	91.3 Å²
Heavy Atom Count	25
Formal Charge	0
Complexity	468
Isotope Atom Count	0
Defined Atom Stereocenter Count	1
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

Pretomanid is indicated for adults in combination with bedaquiline and linezolid for the treatment of pulmonary forms of nonresponsive multidrug-resistant (MDR), extensively drug-resistant (XDR), and treatment-intolerant forms of pulmonary tuberculosis (TB). It is important to note that the following conditions are not approved indications for pretomanid therapy, according to the FDA: Drug-sensitive (DS) tuberculosis, latent tuberculosis caused by M.tuberculosis, extra-pulmonary tuberculosis caused by M.tuberculosis, and multidrug-resistant TB that is not treatment-intolerant or nonresponsive to conventional TB therapy.

Dovprela is indicated in combination with bedaquiline and linezolid, in adults, for the treatment of pulmonary extensively drug resistant (XDR), or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Treatment of multi-drug-resistant tuberculosis

5 Pharmacology and Biochemistry

5.1 Pharmacology

Pretomanid kills the actively replicating bacteria causing tuberculosis, known as Mycobacterium tuberculosis, and shortens the duration of treatment in patients who suffer from resistant forms of pulmonary TB by killing dormant bacteria. In rodent models of tuberculosis infection, pretomanid administered in a regimen with bedaquiline and linezolid caused a significant reduction in pulmonary bacterial cell counts. A decrease in the frequency of TB relapses at 2 and 3 months after treatment was observed after the administration of this regimen, when compared to the administration of a 2-drug regimen. Successful outcomes have been recorded for patients with XDR and MDR following a clinical trial of the pretomanid regimen, demonstrating a 90% cure rate after 6 months. **A note on cardiac QT prolongation, hepatotoxicity, and myelosuppression** This drug has the propensity to caused cardiac QT interval prolongation and significant hepatotoxicity, as well as myelosuppression. Caution must be observed during the administration of this drug.

5.2 ATC Code

J04

J - Antiinfectives for systemic use

J04 - Antimycobacterials

J04A - Drugs for treatment of tuberculosis

J04AK - Other drugs for treatment of tuberculosis

J04AK08 - Pretomanid

5.3 Absorption, Distribution and Excretion

Absorption

This drug is absorbed in the gastrointestinal tract. The steady-state Cmax of pretomanid was estimated to be 1.7 g/mL after a single 200mg oral dose. In a separate pharmacokinetic modeling study, the Cmax of a 200mg dose was 1.1 g/ml. Tmax in a study of healthy subjects in the fed or unfed state was achieved within 4 to 5 hours. The AUC in the same study was found to be about 28.1 ghr/mL in the fasted state and about 51.6 ghr/mL in the fed state, showing higher absorption when taken with high-calorie and high-fat food.

Route of Elimination

Healthy adult male volunteers were administered a 1,100 mg oral dose of radiolabeled pretomanid in one pharmacokinetic study. An average of about 53% of the radioactive dose was found to be excreted in the urine. Approximately 38% was measured mainly as metabolites in the feces. A estimated 1% of the radiolabeled dose was measured as unchanged drug in the urine.

Volume of Distribution

A pharmacokinetic modeling study estimated the volume of distribution at 130 5L. A pharmacokinetic study in healthy volunteers determined a volume of distribution of about 180 51.3L in fasted state and 97.0 17.2L in the fed state.

Clearance

The clearance of pretomanid in a pharmacokinetic simulation study has been estimated at 4.8 0.2 liters/h. According to the FDA label, the clearance of a single 200 mg oral dose of pretomanid is estimated to be 7.6 liters/h in the fasted state, and 3.9 liters/h in the fed state.

5.4 Metabolism/Metabolites

Various reductive and oxidative pathways are responsible for pretomanid metabolism, with no single major metabolic pathway identified. According to in vitro studies, CYP3A4 is responsible for a 20% contribution to the metabolism of pretomanid.

5.5 Biological Half-Life

The elimination half-life was determined to be 16.9-17.4 hours in a pharmacokinetic study of healthy subjects. An FDA briefing document reports a half-life of 18 hours.

5.6 Mechanism of Action

Pretomanid is a prodrug which is metabolically activated by a nitroreductase enzyme, known as Ddn, producing various active metabolites that are responsible for its other therapeutic actions, particularly the induction of nitric oxide. The nitroreductase enzyme which activates pretomanid is deazaflavin dependent and relies on reduced cofactor F420. Reduction of F420 occurs via the enzyme glucose-6-phosphate dehydrogenase. Reduction of pretomanid's imidazole ring at the C-3 position causes the formation of the metabolites, which include a des-nitro derivative. The formation of this derivative leads to increased levels of nitric oxide, leading to bactericidal activities under anaerobic conditions via its action as a bacterial respiratory poison. Bactericidal activity against anaerobes is reported to be associated with a shortened duration of antibiotic treatment. Pretomanid exerts aerobic bactericidal effects through its inhibitory actions on bacterial cell wall mycolic acid biosynthesis. This allows for the killing of actively replicating Mycobacterium tuberculosis bacteria, resulting in the treatment of active tuberculosis infection. The molecular mechanism of the above bactericidal effects is poorly understood at this time, but may involve effects exerted on various genes that affect the cell wall, including the fasI and fasII as well as the efpA and iniBAC operons. Other possible targets include the genes of the cyd operon. The clinical effects of the above target relations are unknown at this time.

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