PosaconazoleSterol C14ɑ demethylase inhibitor CAS# 171228-49-2 |
- Posaconazole hydrate
Catalog No.:BCC4234
CAS No.:1198769-38-8
Quality Control & MSDS
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Chemical structure
3D structure
| Cas No. | 171228-49-2 | SDF | Download SDF |
| PubChem ID | 468595 | Appearance | Powder |
| Formula | C37H42F2N8O4 | M.Wt | 700.78 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | SCH 56592 | ||
| Solubility | DMSO : 50 mg/mL (71.35 mM; Need ultrasonic) | ||
| Chemical Name | 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one | ||
| SMILES | CCC(C(C)O)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OCC5CC(OC5)(CN6C=NC=N6)C7=C(C=C(C=C7)F)F | ||
| Standard InChIKey | RAGOYPUPXAKGKH-XAKZXMRKSA-N | ||
| Standard InChI | InChI=1S/C37H42F2N8O4/c1-3-35(26(2)48)47-36(49)46(25-42-47)31-7-5-29(6-8-31)43-14-16-44(17-15-43)30-9-11-32(12-10-30)50-20-27-19-37(51-21-27,22-45-24-40-23-41-45)33-13-4-28(38)18-34(33)39/h4-13,18,23-27,35,48H,3,14-17,19-22H2,1-2H3/t26-,27+,35-,37-/m0/s1 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | Posaconazole is an inhibitor of C14ɑ demethylase with IC50 value of 0.25 nM. | |||||
| Targets | C14ɑ demethylase | |||||
| IC50 | 0.25 nM | |||||
| Cell experiment: [1] | |
| Cell lines | 25 strains of Coccidioides immitis |
| Preparation method | The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months. |
| Reacting condition | MIC: 0.5 μg/ml, 48 hours |
| Applications | Posaconazole was tested in RPMI 1640 with L-glutamine and morpholinepropanesulfonic acid buffer at a concentration of 165 mM. The final concentration of the drug was 0.015 to 8 μg/ml. The MICs were read at 24 and 48 h. The posaconazole MICs ranged from 0.25 to 1 μg/ml, and the geometric mean posaconazole MIC was 0.5 μg/ml. The posaconazole MICs at which 50 of the isolates tested were inhibited (MIC50) and the MIC90 were 0.5 and 1 μg/ml, respectively. |
| Animal experiment: [2] | |
| Animal models | Male BALB/c mice |
| Dosage form | Oral administration, 5, 15, or 30 mg/kg twice per day, for 7 days |
| Application | Mice were rendered neutropenic with single doses of 5-fluorouracil and with cyclophosphamide one day before infection. This treatment reduced the neutrophil count. Mice were infected intravenously using a 0.2-ml volume of the inoculums. The antifungal agent treatment began 1 day after infection. The survival of posaconazole recipients increased significantly in a dose-dependent manner over that of the controls, with 60 to 83% survival at the 30-mg/kg twice-daily dose. Posaconazole doses of 15 and 30 mg/kg significantly lowered counts in tissue. Posaconazole at a dose of 30 mg/kg reduced many counts to undetectable levels. |
| Other notes | Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
| References: [1] González G M, Tijerina R, Najvar L K, et al. In vitro and in vivo activities of posaconazole against Coccidioides immitis. Antimicrobial agents and chemotherapy, 2002, 46(5): 1352-1356. [2] Sun Q N, Najvar L K, Bocanegra R, et al. In vivo activity of posaconazole against Mucor spp. in an immunosuppressed-mouse model. Antimicrobial agents and chemotherapy, 2002, 46(7): 2310-2312. | |
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Posaconazole, also known as SCH 56592 or Noxafil, is a novel triazole antifungal compound that potently inhibits 14α-demethylation in a variety of fungi, including Candida (C. albicans C43, C. albicans C288, C. albicans C600 and C. albicans C248) and Aspergillus (A. fumigatus ND158 and A. flavus ND134), with half maximal inhibition concentration IC50 of 0.007 μg/ml, 0.06 μg/ml, 0.2 μg/ml, 0.3 μg/ml, 0.03 μg/ml and 0.03 μg/ml respectively [1].
Posaconzole, an itraconzole derivative with fluorine replacing chlorine in the phenyl ring and hydroxylation in the side chain, binds to the heme cofactor on the active site of 14α-demethylase, which converts lanosterol to 14α-dimethy lanosterol, resulting in the disruption of the integrity and function of the fungal cell membrane and inhibition of fungal growth [2].
References:
[1] Hanan K. Munayyer, Paul A. Mann, Andrew S. Chau, Taisa Yarosh-Tomaine, Jonathan R. Greene, Roberta S. Hare, Larry Heimark, Robert E. Palermo, David Loebenberg and Paul M. McNicholas. Posaconazole is a potent inhibitor of sterol 14α-demethylation in yeasts and molds. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY. 2004; 48(10): 3690-3696
[2] Daryl S. Schiller and Horatio B. Fung. Posaconazole: an extended-spectrum triazole antifungal agent. Clinical Therapeutics. 2007; 29(9): 1862-1886
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Prophylaxis with Isavuconazole or Posaconazole Protects Immunosuppressed Mice from Pulmonary Mucormycosis.[Pubmed:28264840]
Antimicrob Agents Chemother. 2017 Apr 24;61(5). pii: AAC.02589-16.
We assessed prophylactic or continuous therapy of isavuconazole, Posaconazole, or voriconazole in treating pulmonary murine mucormycosis. In the prophylaxis studies, only isavuconazole treatment resulted in significantly improved survival and lowered tissue fungal burden of immunosuppressed mice infected with Rhizopus delemar. In the continuous treatment studies, isavuconazole and Posaconazole, but not voriconazole, equally prolonged survival time and lowered tissue fungal burden compared to placebo-treated mice. These results support the use of isavuconazole and Posaconazole in prophylaxis treatment.
Hyperlipidemia Alters the Pharmacokinetics of Posaconazole and Vincristine Upon Co-Administration in Rats.[Pubmed:28299646]
Drugs R D. 2017 Jun;17(2):287-296.
OBJECTIVES: Co-administration of Posaconazole (PSZ) and vincristine (VCR) in the treatment of patients with acute lymphoblastic leukemia increases the neurotoxicity of VCR. Our aim is to study the effect of increased lipoprotein levels on the pharmacokinetics of PSZ and VCR upon co-administration in rats. METHODS: Rats were assigned to three groups, normolipidemic (NL), intermediate hyperlipidemic (IHL), and extreme hyperlipidemic (HL) groups. All rats were administered PSZ orally followed by VCR intravenously 4 h later. For the pharmacokinetic study, serial plasma samples were collected over 96 h and for tissue distribution study; plasma, lung, and liver tissues were collected over 48 h post oral dosing. RESULTS: Posaconazole showed higher plasma concentrations than VCR at all time points. Co-administration of VCR with PSZ reduced PSZ weight normalized oral clearance, increased PSZ area under the plasma concentration-time curve (AUC) from time zero to infinity, showed higher PSZ liver concentrations, and increased VCR volume of distribution of the central compartment. Upon increasing the lipoprotein levels, PSZ showed higher plasma availability and delayed tissue distribution, whereas VCR had shown a significant decrease in PSZ AUC0-24h, AUC0-tlast, and AUCo-inf (NL = IHL > HL) and a significant increase in the volume of distribution (NL = IHL < HL). Vincristine has shown higher tissue uptake and concentrations. CONCLUSION: Monitoring cholesterol and triglyceride levels in patients with acute lymphoblastic leukemia is advisable to decrease VCR neurological side effect incidences and delay the activity of both PSZ and VCR.
Clinical effectiveness of early posaconazole suspension pre-emptive therapy in lung transplant recipients: The Alfred's experience.[Pubmed:28369489]
J Antimicrob Chemother. 2017 Jul 1;72(7):2089-2092.
Objectives: This study describes the clinical outcomes and therapeutic drug monitoring (TDM) following Posaconazole suspension pre-emptive therapy in lung transplant (LTx) recipients. Methods: This was a single-centre, retrospective cohort study evaluating Posaconazole suspension pre-emptive therapy in LTx recipients between January 2009 and December 2015. Results: Forty-two LTx recipients were prescribed Posaconazole suspension pre-emptively. Aspergillus fumigatus was the most commonly isolated fungal organism. Of the patients receiving Posaconazole suspension as the initial antifungal post-LTx, 93% had eradication of colonization at 6 months after commencing therapy. In contrast, only 61% had eradication of fungal colonization when Posaconazole suspension was administered following initial therapy with voriconazole. Posaconazole suspension appeared to be well tolerated, although one case was curtailed following concern about abnormal liver function and another due to nausea/vomiting. TDM was performed in 37 patients. The initial median (IQR) trough plasma concentration ( C min ) following 400 mg twice-daily Posaconazole suspension was 0.78 (0.46-1.19) mg/L. Doses beyond 800 mg daily did not appear to result in a higher median C min. Conclusions: Early initiation of Posaconazole suspension pre-emptive therapy in LTx recipients appears to be well tolerated and may potentially afford favourable clinical outcomes.
Efficacy, safety and feasibility of antifungal prophylaxis with posaconazole tablet in paediatric patients after haematopoietic stem cell transplantation.[Pubmed:28258343]
J Cancer Res Clin Oncol. 2017 Jul;143(7):1281-1292.
PURPOSE: Paediatric recipients of haematopoietic stem cell transplantation (HSCT) have a high risk for invasive fungal infections. Posaconazole oral suspension has proven to be effective in antifungal prophylaxis in adult and paediatric patients. A new Posaconazole tablet formulation with absorption independent of the gastric conditions was approved by the FDA in 2013. This is the first report on the use of Posaconazole tablets in paediatric patients. METHODS: This single-centre study included 63 paediatric patients with haemato-oncological malignancies who received Posaconazole for antifungal prophylaxis after HSCT. They were analysed for efficacy, feasibility and the safety of Posaconazole. Out of 63 patients, 31 received Posaconazole oral suspension and 32 received Posaconazole tablets up to 200 days after transplantation. Analyses of the Posaconazole trough levels were determined. RESULTS: No possible, probable or proven invasive fungal infection was observed in either group. Posaconazole trough levels were significantly higher in the tablet group than in the suspension group at all analysed time points. Drug-related adverse events were similarly low in both groups. CONCLUSIONS: Posaconazole tablets are effective in preventing invasive fungal infections in paediatric patients. As early as day 3 after starting Posaconazole tablets, over 50% of the Posaconazole trough levels were >500 ng/mL, while this was observed on day 14 after start with Posaconazole suspension. The administration of Posaconazole tablets was safe, effective and feasible as antifungal prophylaxis in paediatric patients after HSCT.
