Identification

Name
Posizolid
Accession Number
DB04850  (DB09032)
Type
Small Molecule
Groups
Investigational
Description

Posizolid (AZD2563) is an oxazolidinone antibiotic. In July 2002, after completion of phase I trials in December 2001, AstraZeneca announced that they were no longer pursuing the development of Posizolid, presumably due to negative trial results (though no results were reported).

Structure
Thumb
Synonyms
Not Available
External IDs
AZD-2563 / AZD-5847 / AZD2563 / AZD5847
Categories
UNII
82V2M8K24R
CAS number
252260-06-3
Weight
Average: 465.41
Monoisotopic: 465.134756354
Chemical Formula
C21H21F2N3O7
InChI Key
HBUJYEUPIIJJOS-PBHICJAKSA-N
InChI
InChI=1S/C21H21F2N3O7/c22-15-7-13(26-9-14(33-21(26)30)11-31-18-3-6-32-24-18)8-16(23)19(15)12-1-4-25(5-2-12)20(29)17(28)10-27/h1,3,6-8,14,17,27-28H,2,4-5,9-11H2/t14-,17+/m1/s1
IUPAC Name
(5R)-3-(4-{1-[(2S)-2,3-dihydroxypropanoyl]-1,2,3,6-tetrahydropyridin-4-yl}-3,5-difluorophenyl)-5-[(1,2-oxazol-3-yloxy)methyl]-1,3-oxazolidin-2-one
SMILES
OC[C@H](O)C(=O)N1CCC(=CC1)C1=C(F)C=C(C=C1F)N1C[C@H](COC2=NOC=C2)OC1=O

Pharmacology

Indication

For the treatment of gram-positive infections, including multiresistant strains.

Pharmacodynamics

AZD2563 is an oxazolidinone antibiotic. Oxazolidinones inhibit protein synthesis by binding at the P site at the ribosomal 50S subunit. Resistance to other protein synthesis inhibitors does not affect oxazolidinone activity, however rare development of oxazolidinone resistance cases, associated with 23S rRNA alterations during treatment have been reported.

Mechanism of action

AZD2563 selectively inhibits bacterial protein synthesis through binding to sites on the bacterial ribosome and prevents the formation of a functional 70S-initiation complex. Specifically, AZD2563 binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process.

TargetActionsOrganism
A23S rRNA
antagonist
blocker
Enteric bacteria and other eubacteria
UAmine oxidase [flavin-containing] ANot AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

Clinical signs of acute toxicity lead to decreased activity, ataxia, vomiting and tremors.

Affected organisms
  • Mycobacterium tuberculosis
  • Gram-positive Bacteria
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
BenzylpenicillinThe excretion of Benzylpenicillin can be decreased when combined with Posizolid.
BosentanThe excretion of Bosentan can be decreased when combined with Posizolid.
CaspofunginThe excretion of Caspofungin can be decreased when combined with Posizolid.
Conjugated estrogensThe excretion of Conjugated estrogens can be decreased when combined with Posizolid.
DinoprostoneThe excretion of Dinoprostone can be decreased when combined with Posizolid.
EnalaprilThe excretion of Enalapril can be decreased when combined with Posizolid.
EzetimibeThe excretion of Ezetimibe can be decreased when combined with Posizolid.
FexofenadineThe excretion of Fexofenadine can be decreased when combined with Posizolid.
FluvastatinThe excretion of Fluvastatin can be decreased when combined with Posizolid.
LiothyronineThe excretion of Liothyronine can be decreased when combined with Posizolid.
Food Interactions
Not Available

References

General References
  1. Ednie LM, Jacobs MR, Appelbaum PC: Anti-anaerobic activity of AZD2563, a new oxazolidinone, compared with eight other agents. J Antimicrob Chemother. 2002 Jul;50(1):101-5. [PubMed:12096013]
  2. Wookey A, Turner PJ, Greenhalgh JM, Eastwood M, Clarke J, Sefton C: AZD2563, a novel oxazolidinone: definition of antibacterial spectrum, assessment of bactericidal potential and the impact of miscellaneous factors on activity in vitro. Clin Microbiol Infect. 2004 Mar;10(3):247-54. [PubMed:15008947]
  3. Howe RA, Wootton M, Noel AR, Bowker KE, Walsh TR, MacGowan AP: Activity of AZD2563, a novel oxazolidinone, against Staphylococcus aureus strains with reduced susceptibility to vancomycin or linezolid. Antimicrob Agents Chemother. 2003 Nov;47(11):3651-2. [PubMed:14576139]
  4. Balasubramanian V, Solapure S, Iyer H, Ghosh A, Sharma S, Kaur P, Deepthi R, Subbulakshmi V, Ramya V, Ramachandran V, Balganesh M, Wright L, Melnick D, Butler SL, Sambandamurthy VK: Bactericidal activity and mechanism of action of AZD5847, a novel oxazolidinone for treatment of tuberculosis. Antimicrob Agents Chemother. 2014;58(1):495-502. doi: 10.1128/AAC.01903-13. Epub 2013 Nov 4. [PubMed:24189255]
  5. Link [Link]
External Links
PubChem Compound
213049
PubChem Substance
175426861
ChemSpider
184741
ChEMBL
CHEMBL131854
Wikipedia
Posizolid

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHealthy Volunteers1
1CompletedTreatmentHealthy Volunteers1
2CompletedTreatmentTuberculosis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.71 mg/mLALOGPS
logP1.06ALOGPS
logP0.78ChemAxon
logS-2.8ALOGPS
pKa (Strongest Acidic)12.4ChemAxon
pKa (Strongest Basic)-1.8ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area125.57 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity109.52 m3·mol-1ChemAxon
Polarizability44.18 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.952
Blood Brain Barrier+0.5501
Caco-2 permeable-0.6145
P-glycoprotein substrateSubstrate0.6905
P-glycoprotein inhibitor IInhibitor0.7726
P-glycoprotein inhibitor IIInhibitor0.5188
Renal organic cation transporterNon-inhibitor0.8467
CYP450 2C9 substrateNon-substrate0.8807
CYP450 2D6 substrateNon-substrate0.8229
CYP450 3A4 substrateSubstrate0.5849
CYP450 1A2 substrateNon-inhibitor0.7627
CYP450 2C9 inhibitorNon-inhibitor0.7437
CYP450 2D6 inhibitorNon-inhibitor0.8141
CYP450 2C19 inhibitorNon-inhibitor0.7377
CYP450 3A4 inhibitorNon-inhibitor0.6273
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.812
Ames testNon AMES toxic0.5366
CarcinogenicityNon-carcinogens0.8213
BiodegradationNot ready biodegradable0.9809
Rat acute toxicity2.6132 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.636
hERG inhibition (predictor II)Inhibitor0.8159
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as fluorobenzenes. These are compounds containing one or more fluorine atoms attached to a benzene ring.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Halobenzenes
Direct Parent
Fluorobenzenes
Alternative Parents
Alkyl aryl ethers / Oxazolidinones / Aryl fluorides / Monosaccharides / Hydropyridines / Tertiary carboxylic acid amides / Carbamate esters / Isoxazoles / Heteroaromatic compounds / Secondary alcohols
show 11 more
Substituents
Alkyl aryl ether / Fluorobenzene / Aryl fluoride / Aryl halide / Hydropyridine / Monosaccharide / Oxazolidinone / Azole / Heteroaromatic compound / Isoxazole
show 25 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

1. 23S rRNA
Kind
Nucleotide
Organism
Enteric bacteria and other eubacteria
Pharmacological action
Yes
Actions
Antagonist
Blocker
References
  1. Balasubramanian V, Solapure S, Iyer H, Ghosh A, Sharma S, Kaur P, Deepthi R, Subbulakshmi V, Ramya V, Ramachandran V, Balganesh M, Wright L, Melnick D, Butler SL, Sambandamurthy VK: Bactericidal activity and mechanism of action of AZD5847, a novel oxazolidinone for treatment of tuberculosis. Antimicrob Agents Chemother. 2014;58(1):495-502. doi: 10.1128/AAC.01903-13. Epub 2013 Nov 4. [PubMed:24189255]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Serotonin binding
Specific Function
Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral...
Gene Name
MAOA
Uniprot ID
P21397
Uniprot Name
Amine oxidase [flavin-containing] A
Molecular Weight
59681.27 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. AstraZeneca: AZD5847 Oxazolidinone for the treatment of Tuberculosis [File]

Drug created on October 18, 2007 16:53 / Updated on October 01, 2018 13:56