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TAK-599, a novel N-Phosphono type prodrug of anti-MRSA cephalosporin T-91825: synthesis, physicochemical and pharmacological properties
- Source :
- Bioorganic & Medicinal Chemistry. 11:2427-2437
- Publication Year :
- 2003
- Publisher :
- Elsevier BV, 2003.
-
Abstract
- Crystalline 1 (TAK-599) is a novel N-phosphono prodrug of anti-methicillin-resistant Staphylococcus aureus (MRSA) cephalosporin 2a (T-91825) that has high affinity for penicillin-binding protein (PBP) 2' (IC(50); 0.90 microg/mL) and shows potent in vitro anti-MRSA activity (MIC against MRSA N133; 1.56 microg/mL), comparable to that of vancomycin (1.56 microg/mL). Although 2a had insufficient water solubility (2.3 mg/mL) for parenteral administration, 1 showed excellent water solubility (>100 mg/mL, pH 7) as well as good chemical stability in the solid state and solution. In pharmacokinetic studies, when 1 was administered intravenously to rats and monkeys, it was rapidly converted into 2a in the blood. These results show that 1 (TAK-599) is a highly promising parenteral cephalosporin targeted for MRSA infection.
- Subjects :
- Male
Staphylococcus aureus
Stereochemistry
medicine.drug_class
Clinical Biochemistry
Cephalosporin
Pharmaceutical Science
Microbial Sensitivity Tests
Muramoylpentapeptide Carboxypeptidase
Pharmacology
medicine.disease_cause
Biochemistry
Chemical synthesis
Mice
Structure-Activity Relationship
Bacterial Proteins
Pharmacokinetics
Drug Discovery
medicine
Animals
Penicillin-Binding Proteins
Ceftaroline fosamil
Prodrugs
Molecular Biology
Antibacterial agent
Mice, Inbred ICR
Chemistry
Organic Chemistry
biochemical phenomena, metabolism, and nutrition
Prodrug
Anti-Bacterial Agents
Cephalosporins
Rats
Macaca fascicularis
Hexosyltransferases
Solubility
Peptidyl Transferases
Molecular Medicine
Vancomycin
Methicillin Resistance
Carrier Proteins
medicine.drug
Subjects
Details
- ISSN :
- 09680896
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....e9aa635b1b4bcdfd603afaf2b813bebd