Products Description
English name: Daptomycin
CAS number:103060-53-3
Molecular formula: C72H101N17O26
Molecular weight: 1,620.67
EINECS No.: 600-389-2
Related categories:
materia medica; crude drug; antibiotic; Medical intermediates; Other classes of antibiotics; acridine; Fermentation class; Microbial metabolites; Cyclic lipopeptide antibiotics; Organic raw materials; Pharmaceutical API; raw material; Small-molecule inhibitors; Small-molecule inhibitors, natural products; Chemical intermediates; Pharmaceutical and chemical industry; control article; Control-impurity control; crude drug API; materia medica; Medical raw materials-raw materials; Control article-Chinese medicine control; Pharmaceutical API scientific research raw materials; Medicine, pesticide, and dye intermediates; Supof Chemicalbook preparation; API/ intermediate; Chemical drug impurities-daptomycin; Antidrug intermediate; biochemical engineering; General biochemical reagent-Antibiotics; chemical reagent; reagent; chemical raw material; Antibacterial; Intermediates&FineChemicals; Pharmaceuticals; ChiralReagents; Heterocycles; API; VIREAD; Inhibitors.
The Mol file, 103060-53-3.mol
Structural formula:
The nature of daptomycin
Melting point: 202-204? C
Boiling point: 2078.2 ± 65.0 C (Predicted)
Density: 1.45±0.1g/cm3 (Predicted)
Flash point: 87℃
Storage conditions: Sealedindry, Storeinfreezer, under-2Chemicalbook0 C
Solubility: soluble in methanol: 5 mg/mL
Form: powder
Aciity coefficient (pK a): 4.00 ± 0.10 (Predicted)
Color: colorless to pale yellow
Biological source: Streptomycesroseosporus
Maximum wavelength: (λ max) 260nm (EtOH) (let.)
Merck14,2823
Stability: Stable for 2 years from the date of purchase. The DMSO or ethanol solution can be stored at-20℃ for up to 3 months.InChIKey:DOAKLVKFURWEDJ-RWDRXURGSA-N
Use and synthesis methods of daptomycin
Antibiotic
Daptomycin is a completely new structured cyclic lipopeptide antibiotic extracted from the fermentation broth of Streptomyces (S.reseosporus), Discovered by Eli Lilly in the 1980s, Was successfully developed by Cubist Pharmaceuticals in 1997, Not only does it have a novel chemical structure, And its mode of action is different from any approved antibiotic: by disrupting the transport of amino acids to the cell membrane, Thus hindering the biosynthesis of bacterial cell wall peptide poly Chemicalbook sugars, Altering the properties of the cell plasma membrane, Can disrupt the bacterial cell membrane function in multiple aspects, And rapidly killed the Gram-positive bacteria. In addition to acting on most clinically relevant Gram-positive bacteria, daptomycin is more importantly potent in vitro against isolates with resistance properties such as methicillin (methicillin), vancomycin and linezolane. This property is of great clinical significance for critically ill infected patients.
Daptomycin was first approved for the treatment of severe skin infections in September 2003 and for infectious diseases in March 2006.
It was approved by the European Commission in January 2006 for the treatment of complex skin and soft tissue infections caused by certain Gram-positive bacteria.
On September 6,2007, Cubist Pharmaceuticals announced that the EU has approved its antimicrobial drug daptomycinforinjection (CChemicalbookubicin) for injection for the treatment of right heart infection endocarditis caused by Glutococcus aureus and Staphylococcus aureus bacteremia associated with right heart infection endocarditis or complex skin and soft tissue infections.
On July 29,2010, the U. S. Food and Drug Administration (FDA) released information to alert patients and medical professionals that the use of the intravenous drug daptomycin (daptomycin, manufactured by Cubist Pharmaceutical Company, trade name ChemicalbookCubicin) may cause oncocytic pneumonia. Oncocytic pneumonia is a rare and very serious disease, whose symptoms mainly include fever, cough, shortness of breath, and dyspnea.
The alias for daptomycin is called daptomycin.
Bacteriostasic activity;bacteriostasis
Studies have showed that the antibacterial spectrum activity of daptomycin is similar to that of vancomycin, mainly with a strong antibacterial effect on Gram-positive cocci, such as MIC = 0.125 to 0.5 μg/ml for staphylococcus spp, MIC = 0.06 to 0.5 μg/ml for Gram spp, and ChemicalbookMIC = 0.25 to 2.0 μg/ml for enterococci. Daptomycin also has a broad spectrum of antimicrobial activity against Gram-positive anaerobes, with MIC = 0.12 μg/ml against digestive Streptococcus spp., spp.MIC=0.5 μg/ml against Clostridium, and Lactobacillus spp.MIC=1 μg/ml.
Daptomycin has good antibacterial activity against resistant bacteria of various antibiotics, For example, MIC = 0.06 ~ 0.5 μg/ml for methicillin-resistant Staphylococcus species (MRSA), MIC = 0.0625 to 1 μg/ml for methicillin resistant superStaphylococcus, MIC = 0.12 to 0.5 μg/ml for oxacillin-resistant Staphylococcus Chemicalbook, MIC = 2.5 μg/ml for enterococci highly resistant to aminoglycoside antibiotics, MIC = 0.5 to 1 μg/ml for GmrBIa-Enterococci, MIC = 1 to 2 μg/ml for resistant enterococci.
Toxicology
According to data provided by Lilly Pharma Laboratory, daptomycin is a relatively safe and low-toxic antibiotic. LD 50 = 142-159 mg / kg (dog 200mg / kg) in mice, weight loss, appetite loss and the LD 50 = 25-200 mg / kg in monkeys. The main symptoms are lethargy, muscle weakness, ataxia, elevated creatinine phosphokinase, and slight irritation after skin and eye contact. After one month of mouse administration (intravenous injection) at 25-125 mg / kg, the degeneration of renal cortex tube Chemicalbook-shaped epidermis and skeletal muscle occurred in each dose group. In the 150mg / kg dose group, sciatic nerve degeneration also appeared, but it did not affect fertility and had no teratogenic effect. In the 6-month chronic toxicity experiment, dogs were administered intravenous daptomycin at a dose of 2,10,40mg / (kg d). Only the 40mg / (kg d) group showed loss of geniculis and moderate neuroaxon degeneration and mild neurotransmission velocity, but function was normalized after 2 weeks. One dose of 2.0mg / kg had no effect on human muscle and nervous system.
Mechanism of action
In the daptomycin (black) structure, the ring structure is polar end and the tail is non-polar end, which is close to the structure of phospholipid molecules. Under the action of calcium ions, similar with PG phospholipids (yellow) on the cell membrane, inserted into the bilayer, oligomerization forms the functional pore of octahedral, cell membrane destruction, K + efflux, fine Chemicalbook cell depolarization, this loss of cell membrane potential inhibits the synthesis of DNA, RNA and protein, and eventually leads to bacterial cell death. This mechanism of action of daptomycin is different from any other antibiotic, even if amphotericin B acts on the cell membrane.
The mechanism of action of daptomycin is different from other antibiotics, which hinders the biosynthesis of peptidoglycan in the bacterial cell wall by changing the nature of the cell plasma membrane. In addition, it can destroy the cell membrane of bacteria, so it may be difficult for bacteria to develop resistance to daptomycin.
Pharmacokinetics
Six different doses of 0.5~6.0mg/kg and 1.0mg / kg14C-labeled daptomycin showed that daptomycin had longer t1 / 2 (t1 / 2 = 6-8 h), smaller volume of distribution (V=0.1~0.2L/kg) and renal clearance CLr=0.17~0.2ml/ (min kg). Daptomycin basically exists in the form of non-metabolic active agent in the blood, and the kidney is the main metabolic organ, about 78% of daptomycin is excreted from the urine, and the metabolites of daptomycin exist in the urine. The distribution of daptomycin in the body is not completely clear. In patients with sepsis and endocarditis, Chemicalbook of totomycin 3mg / kg every 12h, the peak blood concentration (cmax) averaged 35.45 compared with healthy volunteers, an increased steady-state volume of distribution (Vss = 0.21), and the clearance (CL) increased by 22%.
In vivo activity and clinical applications
This product is mainly used in the treatment of endocarditis, sepsis, peritonitis and urinary tract infection caused by Staphylococcus species, streptococcus species and enterococcus species, especially the endocarditis caused by various drug-resistant strains. Animal experiments have shown that the treatment of endocarditis, peritonitis, pneumonia, medulpitis and other diseases caused by MRSA or other resistant strains is better than or equal to vancomycin, and daptomycin is t1 / 2 long in vivo and has less toxic side effects, so it has considerable clinical application value. In October 1990, the first case of daptomycin to endocarditis caused by aureus-resistant strain was reported. Analysis of the high affinity of daptomycin and the protein (90%), low dose and the pharmacokinetic parameters of the patient are different from those of healthy people, and the pharmacology and clinical application of daptomycin are continuing.
Tolerance
The probability of daptomycin-resistant strains is low, and the resistance is not strong. From streptococcus pneumoniae, Enterococcus, and Staphylococcus, in vitro screening of daptomycin-resistant strains of S. pneumoniae had the highest probability of 1.210-6 (16 MIC), the lowest incidence of resistant strains was 7.010-9 (8MIChemicalbookC), and the general MIC increased by 8 to 32 times. After three passages with medium without antibiotics, resistance decreased to 1 / 2 to 1 / 4, and in the rabbit endocarditis model, 13% of rabbits developed daptomycin-resistant daptomycin Staphylococcus, but the resistance was diminished, suggesting that stabilization of daptomycin resistance may involve multi-point mutations.
Drug interaction
Daptomycin with netemm, amikacin, imipenem, fosfomycin, have synergistic effect, can improve antibacterial activity, with teicoplanin, vancomycin with SmaGmrBla-enterococcus has very good antibacterial activity, Chemicalbook daptomycin and gentamicin with glycopeptide resistant antibiotics streptococcus fecal bacteria also have synergistic effect. This has been demonstrated in animal models. Daptomycin can reduce its nephrotoxicity, the opposite effect of vancomycin.
Use
Medical intermediates for the treatment of concurrent skin and skin structure infections caused by some Gram-positive susceptible strains.
Security information
WGK Germany:3
RTECS number: HB5626000
Customs code: 29419090
Toxicity: LD50 i.v. in mice: 600 mg / kg (Debono)
MSDS information
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