Ceftobiprole

Identification

Name
Ceftobiprole
Accession Number
DB04918
Type
Small Molecule
Groups
Approved, Investigational
Description

Ceftobiprole is an experimental cephalosporin antibiotic with activity against methicillin-resistant Staphylococcus aureus. It was discovered by Basilea Pharmaceutica and is being developed by Johnson & Johnson Pharmaceutical Research and Development. Ceftobiprole is the first cephalosporin to demonstrate clinical efficacy in patients with infections due to methicillin-resistant staphylococci and, if approved by regulatory authorities, is expected to be a useful addition to the armamentarium of agents for the treatment of complicated skin infections and pneumonia.

Structure
Thumb
Synonyms
  • Ceftobiprole Medocaril
External IDs
BAL-9141 / BAL-9141-000 / BAL-9141000 / BAL5788 / BAL9141-000 / RO 63-9141 / RO-63-9141 / RO-639141
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ZefteraPowder, for solution500 mgIntravenousJanssen Pharmaceuticals2008-09-022010-04-23Canada
ZevteraPowder, for solution500 mgIntravenousAvir Pharma Inc2018-03-20Not applicableCanada
Categories
UNII
5T97333YZK
CAS number
209467-52-7
Weight
Average: 534.57
Monoisotopic: 534.110372808
Chemical Formula
C20H22N8O6S2
InChI Key
VOAZJEPQLGBXGO-SDAWRPRTSA-N
InChI
InChI=1S/C20H22N8O6S2/c21-20-24-14(26-36-20)11(25-34)15(29)23-12-17(31)28-13(19(32)33)9(7-35-18(12)28)5-8-2-4-27(16(8)30)10-1-3-22-6-10/h5,10,12,18,22,34H,1-4,6-7H2,(H,23,29)(H,32,33)(H2,21,24,26)/b8-5+,25-11-/t10-,12-,18-/m1/s1
IUPAC Name
(6R,7R)-7-[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(N-hydroxyimino)acetamido]-8-oxo-3-{[(3E,3'R)-2-oxo-[1,3'-bipyrrolidine]-3-ylidene]methyl}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
SMILES
[H][C@@]1(NC(=O)C(=N/O)\C2=NSC(N)=N2)C(=O)N2C(C(O)=O)=C(CS[C@]12[H])\C=C1/CCN(C1=O)[C@]1([H])CCNC1

Pharmacology

Indication

For the treatment of serious bacterial infections in hospitalised patients.

Associated Conditions
Pharmacodynamics

Ceftobiprole, a cephalosporin antibiotic, is active against methicillin-resistant Staphylococcus aureus.

Mechanism of action

Cephalosporins, such as ceftobiprole, are bactericidal and have the same mode of action as other beta-lactam antibiotics (such as penicillins). Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity, especially in Gram-positive organisms. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidases known as penicillin binding proteins (PBPs). PBPs bind to the D-Ala-D-Ala at the end of muropeptides (peptidoglycan precursors) to crosslink the peptidoglycan. Beta-lactam antibiotics mimic this site and competitively inhibit PBP crosslinking of peptidoglycan.

TargetActionsOrganism
UMecANot AvailableStaphylococcus aureus
UPenicillin-binding protein 2xNot AvailableStreptococcus pneumoniae serotype 4 (strain ATCC BAA-334 / TIGR4)
UPeptidoglycan synthase FtsINot AvailableEscherichia coli (strain K12)
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
Not Available
Affected organisms
  • Enteric bacteria and other eubacteria
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcenocoumarolCeftobiprole may increase the anticoagulant activities of Acenocoumarol.
AcetaminophenCeftobiprole may decrease the excretion rate of Acetaminophen which could result in a higher serum level.
Acetylsalicylic acidThe risk or severity of nephrotoxicity can be increased when Acetylsalicylic acid is combined with Ceftobiprole.
AlprazolamCeftobiprole may decrease the excretion rate of Alprazolam which could result in a higher serum level.
AmikacinThe risk or severity of nephrotoxicity can be increased when Amikacin is combined with Ceftobiprole.
AmlodipineCeftobiprole may decrease the excretion rate of Amlodipine which could result in a higher serum level.
AmoxicillinCeftobiprole may decrease the excretion rate of Amoxicillin which could result in a higher serum level.
AmphetamineCeftobiprole may decrease the excretion rate of Amphetamine which could result in a higher serum level.
AmpicillinCeftobiprole may decrease the excretion rate of Ampicillin which could result in a higher serum level.
AuranofinCeftobiprole may decrease the excretion rate of Auranofin which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K: Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. Antimicrob Agents Chemother. 2007 Jul;51(7):2621-4. Epub 2007 Apr 30. [PubMed:17470659]
  2. Noel GJ: Clinical profile of ceftobiprole, a novel beta-lactam antibiotic. Clin Microbiol Infect. 2007 Jun;13 Suppl 2:25-9. [PubMed:17488373]
  3. Yun HC, Ellis MW, Jorgensen JH: Activity of ceftobiprole against community-associated methicillin-resistant Staphylococcus aureus isolates recently recovered from US military trainees. Diagn Microbiol Infect Dis. 2007 Dec;59(4):463-6. Epub 2007 Oct 29. [PubMed:17911001]
  4. Lin G, Appelbaum PC: Activity of ceftobiprole compared with those of other agents against Staphylococcus aureus strains with different resistotypes by time-kill analysis. Diagn Microbiol Infect Dis. 2008 Feb;60(2):233-5. Epub 2007 Nov 7. [PubMed:17997257]
  5. Noel GJ, Strauss RS, Amsler K, Heep M, Pypstra R, Solomkin JS: Results of a double-blind, randomized trial of ceftobiprole treatment of complicated skin and skin structure infections caused by gram-positive bacteria. Antimicrob Agents Chemother. 2008 Jan;52(1):37-44. Epub 2007 Oct 22. [PubMed:17954698]
External Links
PubChem Compound
12993649
PubChem Substance
175426903
ChemSpider
23350302
ChEBI
140407
ChEMBL
CHEMBL520642
Wikipedia
Ceftobiprole
ATC Codes
J01DI01 — Ceftobiprole medocaril
AHFS Codes
  • 08:12.06 — Cephalosporins

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceAntimicrobial Agent / Cephalosporins / Drug Resistance1
1CompletedBasic ScienceBMI >30 kg/m2 / Staphylococcal Skin Infections / Streptococcal Infections1
1CompletedBasic ScienceStaphylococcal Skin Infections / Streptococcal Infections3
1CompletedDiagnosticTotal Hip Replacement Surgery1
1RecruitingTreatmentBacterial Infections1
1TerminatedTreatmentVentilator-associated Bacterial Pneumonia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Powder, for solutionIntravenous500 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.159 mg/mLALOGPS
logP-1.3ALOGPS
logP-4.5ChemAxon
logS-3.5ALOGPS
pKa (Strongest Acidic)-0.89ChemAxon
pKa (Strongest Basic)10.4ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count11ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area203.44 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity131.04 m3·mol-1ChemAxon
Polarizability50.41 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9848
Blood Brain Barrier-0.9231
Caco-2 permeable-0.6329
P-glycoprotein substrateSubstrate0.821
P-glycoprotein inhibitor INon-inhibitor0.8638
P-glycoprotein inhibitor IINon-inhibitor0.9971
Renal organic cation transporterNon-inhibitor0.9155
CYP450 2C9 substrateNon-substrate0.8546
CYP450 2D6 substrateNon-substrate0.7979
CYP450 3A4 substrateNon-substrate0.5567
CYP450 1A2 substrateNon-inhibitor0.686
CYP450 2C9 inhibitorNon-inhibitor0.7322
CYP450 2D6 inhibitorNon-inhibitor0.8646
CYP450 2C19 inhibitorNon-inhibitor0.6778
CYP450 3A4 inhibitorNon-inhibitor0.8981
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9212
Ames testNon AMES toxic0.5598
CarcinogenicityNon-carcinogens0.8598
BiodegradationReady biodegradable0.7278
Rat acute toxicity2.4586 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7721
hERG inhibition (predictor II)Non-inhibitor0.7278
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 cephalosporins. These are compounds containing a 1,2-thiazine fused to a 2-azetidinone to for a oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid moiety or a derivative thereof.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Lactams
Sub Class
Beta lactams
Direct Parent
Cephalosporins
Alternative Parents
N-acyl-alpha amino acids and derivatives / 1,3-thiazines / Pyrrolidine-2-ones / N-alkylpyrrolidines / Thiadiazoles / Tertiary carboxylic acid amides / Heteroaromatic compounds / Ketoximes / Secondary carboxylic acid amides / Amino acids
show 12 more
Substituents
Cephalosporin / N-acyl-alpha amino acid or derivatives / Alpha-amino acid or derivatives / Meta-thiazine / Pyrrolidone / 2-pyrrolidone / N-alkylpyrrolidine / Azole / Ketoxime / Pyrrolidine
show 28 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Staphylococcus aureus
Pharmacological action
Unknown
General Function
Transferase activity, transferring glycosyl groups
Specific Function
Not Available
Gene Name
mecA
Uniprot ID
Q7DHH4
Uniprot Name
MecA
Molecular Weight
76102.075 Da
References
  1. Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K: Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. Antimicrob Agents Chemother. 2007 Jul;51(7):2621-4. Epub 2007 Apr 30. [PubMed:17470659]
Kind
Protein
Organism
Streptococcus pneumoniae serotype 4 (strain ATCC BAA-334 / TIGR4)
Pharmacological action
Unknown
General Function
Penicillin binding
Specific Function
Penicillin-binding proteins (PBPs) function in the late steps of murein biosynthesis. Beta-lactams inactivate the PBPs by acylating an essential serine residue in the active site of these proteins.
Gene Name
pbpX
Uniprot ID
P14677
Uniprot Name
Penicillin-binding protein 2x
Molecular Weight
82312.475 Da
References
  1. Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K: Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. Antimicrob Agents Chemother. 2007 Jul;51(7):2621-4. Epub 2007 Apr 30. [PubMed:17470659]
Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Unknown
General Function
Peptidoglycan glycosyltransferase activity
Specific Function
Essential cell division protein that is required for the synthesis of peptidoglycan at the division septum (PubMed:1103132, PubMed:9614966). Catalyzes the synthesis of cross-linked peptidoglycan fr...
Gene Name
ftsI
Uniprot ID
P0AD68
Uniprot Name
Peptidoglycan synthase FtsI
Molecular Weight
63876.925 Da
References
  1. Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K: Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. Antimicrob Agents Chemother. 2007 Jul;51(7):2621-4. Epub 2007 Apr 30. [PubMed:17470659]

Drug created on October 21, 2007 16:23 / Updated on September 17, 2018 20:56