| Identification | More | [Name]
Entecavir | [CAS]
142217-69-4 | [Synonyms]
ENTECAVIR
Entecavi
ENTECAVIR, 98-102%
entecavir Baraclude
2-Amino-9-[4-hydroxy-3-(hydroxymethyl)-2-methylidene-cyclopentyl]-3H-purin-6-one, Baraclude
2-Amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one
2-Amino-9-[4-hydroxy-3-(hydroxymethyl)-2-methylidene-cyclopentyl]-3H-purin-6-one
Baraclude
SQ 34676 | [EINECS(EC#)]
604-279-5 | [Molecular Formula]
C12H15N5O3 | [MDL Number]
MFCD00907887 | [MOL File]
142217-69-4.mol | [Molecular Weight]
277.28 |
| Chemical Properties | Back Directory | [Appearance]
White to Off-White/Yellow Crystalline Powder | [Melting point ]
249-252°C | [Boiling point ]
661.4±65.0 °C(Predicted) | [density ]
1.81±0.1 g/cm3(Predicted) | [storage temp. ]
-20°C Freezer | [solubility ]
DMSO (Slightly), Methanol (Sparingly) | [form ]
powder | [pka]
14.22±0.60(Predicted) | [color ]
white to beige | [optical activity]
[α]/D +25 to +40°, c = 0.2 in H2O | [Usage]
An oral antiviral drug used in the treatment of hepatitis B infection. A guanine analogue that inhhibits all three steps in the viral replication process | [Stability:]
Hygroscopic | [CAS DataBase Reference]
142217-69-4(CAS DataBase Reference) |
| Hazard Information | Back Directory | [Chemical Properties]
White to Off-White/Yellow Crystalline Powder | [Uses]
An oral antiviral drug used in the treatment of hepatitis B infection. A guanine analogue that inhhibits all three steps in the viral replication process | [Definition]
ChEBI: Guanine substituted at the 9 position by a 4-hydroxy-3-(hydroxymethyl)-2-methylidenecyclopentyl group. A synthetic analogue of 2'-deoxyguanosine, it is a nucleoside reverse transcriptase inhibitor with selective antiviral activity against hepatitis B virus
Entecavir is phosphorylated intracellularly to the active triphosphate form, which competes with deoxyguanosine triphosphate, the natural substrate of hepatitis B virus reverse transcriptase, inhibiting every stage of the enzyme's activity, although it ha
no activity against HIV. It is used for the treatment of chronic hepatitis B. | [Description]
Entecavir is a cyclopentyl guanosine analog launched for the once-daily
oral treatment of chronic hepatitis B virus (HBV) infection, and it is the third
nucleoside or nucleotide analog to be marketed for this indication. Lamivudine, a
deoxythiacytosine analog, and adefovir dipivoxil, a nucleotide analog, have been
marketed since 1998 and 2002, respectively. Entecavir and adefovir are specifically
indicated for HBV, whereas lamivudine is indicated for both HBV and HIV infections.
In mammalian cells, entecavir is efficiently phosphorylated to the active
triphosphate form, which competes with the natural substrate deoxyguanosine
triphosphate and functionally inhibits all three activities of the HBV polymerase:
(1) base priming, (2) reverse transcription of the negative strand from the pregenomic
messenger RNA, and (3) synthesis of the positive strand of HBV DNA.The most common adverse events associated with
the use of entecavir are similar to those typically seen with HBV therapy and
include headache, abdominal pain, diarrhea, fatigue, and dizziness. | [Originator]
BMS (US) | [Brand name]
Baraclude (Bristol-Myers Squibb). | [Pharmaceutical Applications]
An analog of guanosine formulated as tablets and suspension
for oral use. | [Trade name]
Baraclude (BMS)
| [Biochem/physiol Actions]
Entecavir is an antiviral guanine analog that inhibits reverse transcription, DNA replication and transcription in the viral replication process. Entecavir is used to treat hepatitis B. | [Mechanism of action]
Entecavir is a nucleoside analog, or more specifically, a deoxyguanosine analogue that belongs to a class of carbocyclic nucleosides and inhibits reverse transcription, DNA replication and transcription in the viral replication process. | [Pharmacokinetics]
Oral absorption： 100%
Cmax 0.5 mg/kg oral： 4.2 ng/mL
Intracellular half-life： c. 16 h
Volume of distribution： In excess of body water
Plasma protein binding： 13%
Entecavir is rapidly absorbed after administration on an empty stomach, achieving peak plasma concentrations in 1–1.5 h. Plasma steady state is achieved in 6–10 days.
It is renally eliminated. Dosage adjustment is required with impaired creatinine clearance. The drug is not metabolized by cytochrome P450. No drug interactions have been identified. | [Clinical Use]
Treatment of chronic hepatitis B virus infection in patients >16 years of age | [Side effects]
The most common side effects of entecavir: the increase of ALT, fatigue, dizziness, nausea, abdominal pain, abdominal discomfort, abdominal discomfort, liver, muscle, insomnia, rubella and indigestion, also be found in neutrophils decreased slightly.
These adverse reactions were mild to moderate. It also found that, as the same type of antiviral drugs, entecavir and the first generation of antiviral drugs have similar side effects, such as acid poisoning, hepatomegaly, liver fatty degeneration in the withdrawal will appear rebound phenomenon. | [Synthesis]
Several syntheses of entecavir
have been reported and the synthesis described below is
based on the most recent patents in the following scheme.
Commercial sodium cyclopentadienide (50) was treated with
phenyldimethylchlorosilane in anhydrous THF at –78oC. The
resulting silane moiety serves as a masked hydroxyl group
that will be revealed later in the synthetic process. The silylated
product was subsequently reactive with dichloroacetyl
chloride to a 2+2 cycloaddition reaction to give cyclobutanone
51 as crude dark oil. The cyclobutanone 51 was then
opened under a basic condition, and the resulting intermediate
reduced with sodium borohydride at low temperature to
yield racemic free carboxylic acid 52. The racemic 52 was
subjected to chiral resolution with a chiral amine, R, R-(-)-2-
amino-1-(4-nitrophenyl)-1,3-propanediol (53), to give chiral
salt 54 in 99% e.e. and 28% overall yield from the starting
material 50 as crystals. The chiral salt 54 was de-salted and
converted to corresponding methyl ester 55 with sulfuric
acid in methanol. The double bond in compound 55 was then
expoxidized with titanium(IV) isopropoxide/TBHP at –30oC
in dichloromethane to give an epoxyl ester which was selectively
reduced with sodium borohydride in IPA to give epoxyl
diol 56 as light yellow oil. Lithium salt of 2-amino-6-Obenzyl-
oxypurine (57) was added to the epoxide 56 to give
the ring-opening product 58. The vicinal diol moiety of 58
was converted to an alkene by a two-step procedure. Compound
58 was reacted with diethoxymethyl acetate and PPTS
in dichloromethane to give a mixture of dioxolanes as a viscous
brown oil which was subsequently reacted with acetic
anhydride at 120°C for 30 hours to an alkene. Concentrated
HCl was added to the alkene mixture to hydrolyze the 6-
benzyl-oxy group and an 2-N-acetyl group formed in the
previous acetic anhydride reaction to give compound 59 as a
light brown colored product. Finally, compound 59 was converted
to entecavir by protodesilylation of the silane moiety
followed by oxidation to convert the silane moiety to the
hydroxyl group. Therefore, 59 was treated with boron
trifluoride-acetic acid complex in acetic acid at high temperature
and followed by basic hydrogen peroxide oxidation
to give entecavir (VIII).
| [Drug interactions]
Potentially hazardous interactions with other drugs
None known | [Metabolism]
Entecavir is not a substrate, inhibitor or inducer of the
CYP450 enzyme system. Following administration of
14C-entecavir, no oxidative or acetylated metabolites and
minor amounts of the phase II metabolites, glucuronide
and sulfate conjugates, were observed.Entecavir is predominantly eliminated by the kidney:
renal clearance is independent of dose and ranges between
360-471 mL/min suggesting that entecavir undergoes
both glomerular filtration and net tubular secretion. | [storage]
Store at -20°C |
| Questions And Answer | Back Directory | [Pharmacodynamics]
Entecavir is a guanosine nucleoside analogue with selective activity against hepatitis B virus (HBV). It is designed to selectively inhibit the Hepatitis B virus, blocking all three steps in the replication process. Entecavir is more efficient than an older Hepatitis B drug, lamivudine.
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