Adefovir dipivoxil

Bezeichnung:Adefovir dipivoxil

CAS-Nr142340-99-6

Englisch Name:Adefovir dipivoxil

CBNumberCB6237644

SummenformelC20H32N5O8P

Molgewicht501.47

MOL-Datei142340-99-6.mol

Adefovir dipivoxil physikalisch-chemischer Eigenschaften

Schmelzpunkt	98-102°C
Siedepunkt	641.0±65.0 °C(Predicted)
Dichte	1.35±0.1 g/cm3(Predicted)
storage temp.	Keep in dark place,Inert atmosphere,Store in freezer, under -20°C
Löslichkeit	ethanol: soluble50mg/mL
pka	4.16±0.10(Predicted)
Aggregatzustand	solid
Farbe	White to Off-White
Merck	14,151
InChIKey	WOZSCQDILHKSGG-UHFFFAOYSA-N
CAS Datenbank	142340-99-6(CAS DataBase Reference)

Sicherheit

Kennzeichnung gefährlicher	Xn
R-Sätze:	20/21/22
S-Sätze:	36/37
WGK Germany	3
RTECS-Nr.	UA2459362
HS Code	2933.99.8290

Gefahreninformationscode (GHS)

Adefovir dipivoxil Chemische Eigenschaften,Einsatz,Produktion Methoden

R-Sätze Betriebsanweisung:
R20/21/22:Gesundheitsschädlich beim Einatmen,Verschlucken und Berührung mit der Haut.
S-Sätze Betriebsanweisung:
S36/37:Bei der Arbeit geeignete Schutzhandschuhe und Schutzkleidung tragen.
Beschreibung
Adefovir dipivoxil is the first nucleotide analog to be launched in the US as an oral treatment for hepatitis B virus (HBV) infections. It can be easily prepared in 4 steps from adenine. Adefovir dipivoxil acts as a bioavailable ester prodrug which is rapidly hydrolyzed to free adefovir and further anabolized to its active form, adefovir diphosphate, by two intracellular phosphotylation steps. The diphosphate competitively inhibits reverse transcriptase and/or causes chain termination when incorporated into growing DNA. Adefovir dipivoxil has a broad antiviral spectrum against retro-, herpes- and hepadnaviruses. The drug inhibits HBV replication, decreases HBV DNA levels and improves liver histology of patients infected with HBV wild type and resistant to other antivirals such as lamivudine. It also demonstrated activity in hepatitis B”e” antigennegative, or precore mutant, patients and in patients co-infected with HIV. To date, no adefovir dipivoxil-associated resistance mutations have been identified in patients up to 136 weeks with the drug. The oral bioavailability of adefovir after oral administration of its dipivoxil prodrug is approximately 30%. It is mainly excreted unchanged in the urine and its plasma elimination half-life is 4.2 h. However, a long intracellular half-life (17 h) of the active bisphosphorylated metabolite enables once-daily dosing. The most prominent adverse effect of adefovir dipivoxil is nephrotoxicity (which has prevented the drug from being marketed for HIV infections where the drug required administration at higher doses).
Chemische Eigenschaften
White Solid
Originator
Institute of Organic Chemistry and Biochemistry of the Academy of Sciences in the Czech Republic and the REGA Stichting Research (Czech Republic, Belgium)
Verwenden
Adefovir Dipivoxil(Preveon, Hepsera) works by blocking reverse transcriptase, an enzyme that is crucial for the hepatitis B virus (HBV) to reproduce in the body. It is approved for the treatment of chronic hepatitis B in adults with evidence of active vir
Verwenden
A nucleotide analog, useful as an oral reverse transcriptase inhibitor (ntRTI).
Definition
ChEBI: Adefovir pivoxil is an organic phosphonate that is the dipivoxil ester of adefovir. A prodrug for adefovir, an HIV-1 reverse transcriptase inhibitor, adefovir pivoxil is used to treat chronic hepatitis B viral infection. It has a role as a prodrug, an antiviral drug, a DNA synthesis inhibitor, a HIV-1 reverse transcriptase inhibitor and a nephrotoxic agent. It is an organic phosphonate, a member of 6-aminopurines, an ether and a carbonate ester. It is functionally related to an adefovir.
Trademarks
Hepsera (Gilead Sciences).
Allgemeine Beschreibung
Adefovir is an orally active prodrug that is indicated for thetreatment of the chronic form of hepatitis B. The dipivoxil moieties are hydrolyzed by ubiquitous esterases to yieldadefovir, which is phosphorylated by adenylate kinase toyield adefovir diphosphate. This compound is inhibitory atHBV DNA polymerase. In addition, adefovir undergoes incorporationinto viral DNA and causes chain termination.Adefovir is poorly absorbed by the oral route, but the dipivoxilester groups cause the bioavailability to increase toapproximately 60%.
Mechanism of action
Adefovir dipivoxil is an orally active prodrug indicated for the treatment of chronic hepatitis B. The drug is hydrolyzed by extracellular esterases to produce adefovir, which in turn is phosphorylated by adenylate kinase to adefovir diphosphate, which inhibits HBV DNA polymerase. Incorporation of adefovir into viral DNA also leads to DNA chain termination. As shown in Figure 43.9, adefovir dipivoxyl is activated in two steps involving an esterase that exposes a free phosphate group (adefovir), followed by addition of a second phosphate by adenylate kinase to form adefovir diphosphate, the active form of the drug.
Clinical Use
Adefovir dipivoxil joins interferon and lamivudine in the treatment of chronic HBV. It can be used singly or in combination with lamivudine. Early clinical studies indicate benefit of the use of adefovir dipivoxil to treat lamivudine-resistant HBV with a low level of resistant virus developing to monotherapy with adefovir dipivoxil.
Synthese
Steroidal dutasteride (5) was synthesized from 3-oxo-4- androstene-17|?-carboxylic acid (55). Oxidation of 55 with potassium permanganate, sodium periodate and sodium carbonate in refluxing t-butyl alcohol and water gave secosteroid 56 which was cyclized with ammonium acetate in acetic acid to give 4-aza-steroid 57 in good yield. Stereoselective hydrogenation of 57 with H2 over PtO2 in hot acetic acid and in the presence of ammonium acetate yielded saturated azasteroid 58, which was dehydrogenated with DDQ in the presence of bis(trimethylsilyl)trifluoroacetamide (BSTFA) 59 in refluxing dioxane to give 60. Treatment of 60 with thionyl chloride gave the corresponding acyl chloride intermediate, which was then condensed with 2,5- bis(trifluoromethyl)aniline (61) by means of DMAP in heated toluene to give dutasteride (5) in 57% yield from intermediate 60.
Arzneimittelwechselwirkung
Potentially hazardous interactions with other drugs
Use with caution in combination with other nephrotoxins.
Antivirals: avoid concomitant administration with tenofovir
Interferons: use with caution with peginterferon alfa.
Stoffwechsel
Adefovir is poorly absorbed orally, but the bioavailability of adefovir dipivoxil reaches approximately 59%. The drug is absorbed to an equal extent with or without the presence of food. Adefovir is excreted renally unchanged.

Adefovir dipivoxil Upstream-Materialien And Downstream Produkte

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