Posaconazole (T3D3035)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationXML
Record Information
Version2.0
Creation Date2009-07-21 20:28:45 UTC
Update Date2014-12-24 20:25:56 UTC
Accession NumberT3D3035
Identification
Common NamePosaconazole
ClassSmall Molecule
DescriptionPosaconazole is only found in individuals that have used or taken this drug. It is a triazole antifungal drug that is used to treat invasive infections by Candida species and Aspergillus species in severely immunocompromised patients.As a triazole antifungal agent, posaconazole exerts its antifungal activity through blockage of the cytochrome P-450 dependent enzyme, sterol 14alpha-demethylase, in fungi by binding to the heme cofactor located on the enzyme. This leads to the inhibition of the synthesis of ergosterol, a key component of the fungal cell membrane, and accumulation of methylated sterol precursors. This results in inhibition of fungal cell growth and ultimately, cell death.
Compound Type
  • Amine
  • Antibiotic, Antifungal
  • Antifungal Agent
  • Drug
  • Ether
  • Metabolite
  • Organic Compound
  • Organofluoride
  • Synthetic Compound
  • Trypanocidal Agent
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
Noxafil
Chemical FormulaC37H42F2N8O4
Average Molecular Mass700.777 g/mol
Monoisotopic Mass700.330 g/mol
CAS Registry Number171228-49-2
IUPAC Name4-{4-[4-(4-{[(5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-1-[(2S,3S)-2-hydroxypentan-3-yl]-4,5-dihydro-1H-1,2,4-triazol-5-one
Traditional Nameposaconazole
SMILES[H][C@@](C)(O)[C@]([H])(CC)N1N=CN(C1=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C(OCC2([H])CO[C@](CN3C=NC=N3)(C2)C2=C(F)C=C(F)C=C2)C=C1
InChI IdentifierInChI=1S/C37H42F2N8O4/c1-3-35(26(2)48)47-36(49)46(25-42-47)31-7-5-29(6-8-31)43-14-16-44(17-15-43)30-9-11-32(12-10-30)50-20-27-19-37(51-21-27,22-45-24-40-23-41-45)33-13-4-28(38)18-34(33)39/h4-13,18,23-27,35,48H,3,14-17,19-22H2,1-2H3/t26-,27?,35-,37-/m0/s1
InChI KeyInChIKey=RAGOYPUPXAKGKH-AGDNISCASA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as phenylpiperazines. Phenylpiperazines are compounds containing a phenylpiperazine skeleton, which consists of a piperazine bound to a phenyl group.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassDiazinanes
Sub ClassPiperazines
Direct ParentPhenylpiperazines
Alternative Parents
Substituents
  • Phenylpiperazine
  • N-arylpiperazine
  • Phenyltriazole
  • Phenyl-1,2,4-triazole
  • Aminophenyl ether
  • Phenoxy compound
  • Phenol ether
  • Tertiary aliphatic/aromatic amine
  • Aniline or substituted anilines
  • Dialkylarylamine
  • Alkyl aryl ether
  • Fluorobenzene
  • Halobenzene
  • Benzenoid
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl fluoride
  • Triazole
  • Tetrahydrofuran
  • 1,2,4-triazole
  • Heteroaromatic compound
  • Azole
  • Tertiary amine
  • Secondary alcohol
  • Azacycle
  • Oxacycle
  • Ether
  • Dialkyl ether
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Organopnictogen compound
  • Organic oxygen compound
  • Amine
  • Alcohol
  • Organic nitrogen compound
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External DescriptorsNot Available
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point170-172°C
Boiling PointNot Available
SolubilityInsoluble
LogP5.5
Predicted Properties
PropertyValueSource
Water Solubility0.012 g/LALOGPS
logP4.71ALOGPS
logP5.41ChemAxon
logS-4.8ALOGPS
pKa (Strongest Acidic)14.83ChemAxon
pKa (Strongest Basic)3.93ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area111.79 ŲChemAxon
Rotatable Bond Count12ChemAxon
Refractivity200.71 m³·mol⁻¹ChemAxon
Polarizability74.25 ųChemAxon
Number of Rings7ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_1_1) - 70eV, PositiveNot Available2021-10-18View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_1_1) - 70eV, PositiveNot Available2021-10-18View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-001i-0040039200-08b07b2fdb6037d69bad2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0006-0720039000-7e147a828156c564ac332016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-00fr-9371110000-e757e7e4205eb5a2adda2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-014i-9000142000-912e0dd76ed50c57ab1c2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-014i-9010023000-d36da0a08d20809373fa2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-014i-9021020000-0edf495d49e1ace75ed52016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0f89-0000009400-7aa3663db9f13dde9dd32021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0ul0-2000039500-744321dedaaa98dc62f42021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-00di-9012100000-99bb1aa3ffe3935a34a32021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0002-1000009000-66936b5686a8d36e29422021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-07os-2000039000-676d0e7369cae4bdec852021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-00r7-6110279000-edc138c8ce4e6864275f2021-10-11View Spectrum
Toxicity Profile
Route of ExposurePosaconazole is absorbed with a median Tmax of approximately 3 to 5 hours.
Mechanism of ToxicityAs a triazole antifungal agent, posaconazole exerts its antifungal activity through blockage of the cytochrome P-450 dependent enzyme, sterol 14α-demethylase, in fungi by binding to the heme cofactor located on the enzyme. This leads to the inhibition of the synthesis of ergosterol, a key component of the fungal cell membrane, and accumulation of methylated sterol precursors. This results in inhibition of fungal cell growth and ultimately, cell death.
MetabolismPosaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose. Route of Elimination: The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose. Half Life: Posaconazole is eliminated with a mean half-life (t½) of 35 hours (range 20 to 66 hours).
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised as a result of procedures such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD), or due to hematologic malignancies with prolonged neutropenia from chemotherapy. Also for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole. Posaconazole is used as an alternative treatment for invasive aspergillosis, Fusarium infections, and zygomycosis in patients who are intolerant of, or whose disease is refractory to, other antifungals.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsDuring the clinical trials, some patients received posaconazole up to 1600 mg/day with no adverse events noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg BID for 3 days. No related adverse events were noted by the investigator.
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01263
HMDB IDHMDB15392
PubChem Compound ID147912
ChEMBL IDCHEMBL1397
ChemSpider ID130409
KEGG IDNot Available
UniProt IDNot Available
OMIM ID
ChEBI IDNot Available
BioCyc IDNot Available
CTD IDNot Available
Stitch IDPosaconazole
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkPosaconazole
References
Synthesis Reference

Dominic De Souza, “PREPARATION OF POSACONAZOLE INTERMEDIATES.” U.S. Patent US20130203994, issued August 08, 2013.

MSDST3D3035.pdf
General References
  1. Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, Helfgott D, Holowiecki J, Stockelberg D, Goh YT, Petrini M, Hardalo C, Suresh R, Angulo-Gonzalez D: Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007 Jan 25;356(4):348-59. [17251531 ]
  2. Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, Greinix H, Morais de Azevedo W, Reddy V, Boparai N, Pedicone L, Patino H, Durrant S: Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007 Jan 25;356(4):335-47. [17251530 ]
  3. Bhattacharya M, Rajeshwari K, Dhingra B: Posaconazole. J Postgrad Med. 2010 Apr-Jun;56(2):163-7. doi: 10.4103/0022-3859.65281. [20622401 ]
  4. Frampton JE, Scott LJ: Posaconazole : a review of its use in the prophylaxis of invasive fungal infections. Drugs. 2008;68(7):993-1016. [18457464 ]
  5. Schiller DS, Fung HB: Posaconazole: an extended-spectrum triazole antifungal agent. Clin Ther. 2007 Sep;29(9):1862-86. [18035188 ]
  6. Kwon DS, Mylonakis E: Posaconazole: a new broad-spectrum antifungal agent. Expert Opin Pharmacother. 2007 Jun;8(8):1167-78. [17516880 ]
  7. Groll AH, Walsh TJ: Posaconazole: clinical pharmacology and potential for management of fungal infections. Expert Rev Anti Infect Ther. 2005 Aug;3(4):467-87. [16107193 ]
  8. Rachwalski EJ, Wieczorkiewicz JT, Scheetz MH: Posaconazole: an oral triazole with an extended spectrum of activity. Ann Pharmacother. 2008 Oct;42(10):1429-38. doi: 10.1345/aph.1L005. Epub 2008 Aug 19. [18713852 ]
  9. Li Y, Theuretzbacher U, Clancy CJ, Nguyen MH, Derendorf H: Pharmacokinetic/pharmacodynamic profile of posaconazole. Clin Pharmacokinet. 2010 Jun;49(6):379-96. doi: 10.2165/11319340-000000000-00000. [20481649 ]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available