Tedizolid Phosphate Chemical Properties

Melting point:

>235°C (dec.)

Boiling point:

725.6±70.0 °C(Predicted)

Density 

1.75±0.1 g/cm3(Predicted)

storage temp. 

under inert gas (nitrogen or Argon) at 2-8°C

solubility 

DMSO (Slightly, Sonicated)

form 

Solid

pka

1.81±0.10(Predicted)

color 

White to Off-White

Stability:

Hygroscopic

InChIKey

QCGUSIANLFXSGE-GFCCVEGCSA-N

SMILES

O1[C@@H](COP(O)(O)=O)CN(C2=CC=C(C3=CC=C(C4=NN(C)N=N4)N=C3)C(F)=C2)C1=O

Tedizolid Phosphate Usage And Synthesis

A new antibacterial drug

Tedizolid phosphate is a new anti-bacterial drug developed by CUBIST PHARMS company. Tedizolid phosphate is a prodrug of Tedizolid. After oral or intravenous administration, Tedizolid phosphate is converted to Tedizolid by phosphatase. Tedizolid is the second generation of oxazolidinone antibiotics, a protein synthesis inhibitors. binding the 50S subunit of bacterial ribosomes, it can inhibit protein synthesis and play a role of antibacterial. It  is not easy to have  cross-resistance with other types of antibiotics, and has a longer half-life compared to linezolid.
On June 20, 2014, the US Food and Drug Administration (FDA) approved Tedizolid phosphate for use in certain sensitive bacterial-induced adult acute bacterial skin and skin structure infections (ABSSSI), with trade name SIVEXTRO, specification 200 mg. Tedizolid phosphate has been submitted a listing application in Europe and Canada currently, while the drug has not yet listed in China. Tedizolid's listing application is based on clinical trials ESTABLISH 1 and ESTABLISH 2. The results showed that Tedizolid achieved its primary endpoint and secondary endpoint in clinical trials of ABSSSI (defined by the FDA and the European Medicines Agency).
Clinical studies have shown that Tedizolid not only has a better clinical efficacy, and but shortened the treatment cycle by 40% compared with linezolid.
In addition, the study of Tedizolid for hospital acquired/ventilator-associated bacterial pneumonia (HABP/VABP) has entered the clinical phase II.
Analyst Larry Smith predicts the drug will sell more than $ 1 billion by 2020.
This information was edited by Xiao Nan from Chemicalbook (2015-08-14).

Indications

Tedizolid (Tedizolid Phosphate, Tidizolamide) is oxazolidinone compounds for serious Gram-positive bacterial infection treatment:
Acute bacterial skin and skin structure infections and complex skin and soft tissue infections (absssi/cSSTI, IV/oral) (to be approved).
Hospital Acquired/Ventilator-Associated Bacterial Pneumonia (HABP/VABP) (Clinical Phase II).
SIVEXTRO is a class of oxazolidinone-based antimicrobials designed for Acute bacterial skin and skin structure infections (ABSSSI). In order to reduce the development of resistant bacteria and to maintain the effectiveness of SIVEXTRO and other antimicrobial agents, SIVEXTRO should only be used to treat or prevent infections that have been proven or strongly suspected to be bacterial-induced.

Description

Tedizolid phosphate was approved by the US FDA in June 2014 for treatment of acute bacterial skin and skin structure infections caused by susceptible gram-positive pathogens, including MRSA. Tedizolid phosphate was discovered by Dong-A Pharmaceuticals in South Korea and developed in the USA by Cubist Pharmaceuticals (acquired from Trius Therapeutics in 2013, became a wholly owned subsidiary of Merck in 2015). The worldwide commercialization rights for tedizolid phosphate are divided between Cubist in the USA, Canada, and EU, and Bayer in Asia–Pacific, Latin America, and Africa. This second-generation oxazolidinone prodrug is rapidly converted to the active form tedizolid in the presence of endogenous phosphatases. It inhibits bacterial protein synthesis by binding to the 23S ribosomal RNA of the 50S subunit of the ribosome, preventing formation of the 70S ribosomal initiation complex, and is 4-fold to 16-fold more potent against staphylococci and enterococci compared to linezolid. 251 With high oral bioavailability (approximately 90%) and long half-life (approximately 12 hours), tedizolid phosphate is the first oxazolidinone antibiotic which can be dosed once daily either orally or intravenously.

Uses

Tedizolid, known as TR-700, is an oral and i.v administered intracellular antibacterial drug.

Definition

ChEBI: A phosphate monoester resulting from the formal condensation of equimolar amounts of phosphoric acid with the hydroxy group of tedizolid . It is a prodrug of tedizolid, used for the treatment of acute bacterial skin infections caused by certain susceptibl bacteria, including Staphylococcus aureus (including methicillin-resistant strains (MRSA) and methicillin-susceptible strains), various Streptococcus species, and Enterococcus faecalis.

Clinical Use

Reversible non-selective MAO inhibitor:
Antibacterial agent

Side effects

Tedizolid phosphate was well tolerated following the oral administration of a once-daily 200-mg dose for three days. No serious adverse events (AEs) were reported; the most commonly reported AEs were mild bradycardia (n = 2), headache (n = 1), and nausea (n = 1)[1].

Synthesis

Commercial 5-bromo-2-cyanopyridine (260) was treated with sodium azide and ammonium chloride in DMF to produce tetrazole 261, which was isolated by precipitation of the tetrazole ammonium salt. Subsequent methylation with methyl iodide in THF/DMF (3:1) afforded a 3.85:1 mixture of 262 and the corresponding N1-regioisomer. Acidification with 6 M HCl followed by treatment with 50% aqueous NaOH (to pH 10.6) enabled isolation of 262 in 96% isomeric purity; crude 262 was further purified by recrystallization from isopropyl acetate and obtained in 33% yield from 261. A Suzuki reaction of 262 with boronic acid 263 (which was prepared from commercial 4-bromo-3-fluoroaniline (267) as described in Scheme, via carboxybenzyl (Cbz) protection and lithiation/borylation) followed by recrystallization from ethyl acetate produced triaryl system 264. Deprotonation of the carbamate within 264 using lithium hexamethyldisilazide (LiHMDS) followed by reaction with R-(-)-glycidyl butyrate (265) in the presence of 1,3-dimethyl tetrahydropyrimidin-2 (1H)-one (DMPU) generated tedizolide 266 in 85% yield. Reaction with POCl3 in THF at 1¨C2 ?? followed by subjection to sodium hydroxide and subsequent acidification furnished tedizolid phosphate (XXXIII) in 76% yield across the three steps.

Drug interactions

Potentially hazardous interactions with other drugs
Alcohol: some alcoholic and de-alcoholised drinks contain tyramine which can cause hypertensive crisis.
Alpha-blockers: avoid concomitant use with indoramin; enhanced hypotensive effect.
Analgesics: CNS excitation or depression with pethidine, other opioids and nefopam - avoid; increased risk of serotonergic effects and convulsions with tramadol - avoid.
Antidepressants: enhancement of CNS effects and toxicity; avoid MAOIs, SSRIs and vortioxetine for 2 weeks after use; care with all antidepressants.
Antiepileptics: antagonism of anticonvulsant effect; avoid carbamazepine with or within 2 weeks of MAOIs.
Antimalarials: avoid concomitant use with artemether/lumefantrine and piperaquine with artenimol.
Antipsychotics: effects enhanced by clozapine.
Atomoxetine: possible increased risk of convulsions - avoid concomitant use and for 2 weeks after use.
Bupropion: avoid with or for 2 weeks after MAOIs.
Dapoxetine: increased risk of serotonergic effects, avoid with or for 2 weeks after MAOIs.
Dexamfetamine and lisdexamfetamine: risk of hypertensive crisis, avoid with or for 2 weeks after MAOIs.
Dopaminergics: avoid concomitant use with entacapone and tolcapone; hypertensive crisis with levodopa and rasagiline - avoid for at least 2 weeks after stopping MAOI; hypotension with selegiline.
5HT1 agonist: risk of CNS toxicity with sumatriptan, rizatriptan and zolmitriptan - avoid sumatriptan and rizatriptan for 2 weeks after MAOI.
Metaraminol: risk of hypertensive crisis, avoid with or for 2 weeks after MAOIs.
Methyldopa: avoid concomitant use.
Opicapone: avoid concomitant use.
Sympathomimetics: hypertensive crisis with sympathomimetics - avoid.
Tetrabenazine: risk of CNS excitation and hypertension - avoid.

Metabolism

Tedizolid phosphate is converted by endogenous plasma and tissue phosphatases to the microbiologically active moiety, tedizolid.
Tedizolid is eliminated in excreta, primarily as a noncirculating sulfate conjugate. Following single oral administration of [14C]-labelled tedizolid under fasted conditions, the majority of elimination occurred via the liver with 81.5% of the radioactive dose recovered in faeces and 18% in urine.

References

[1] Wong, Elaine, and Saba Rab. “Tedizolid phosphate (sivextro): a second-generation oxazolidinone to treat acute bacterial skin and skin structure infections.”P & T : a peer-reviewed journal for formulary management vol. 39,8 (2014): 555-79.

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