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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

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.

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.

BMS (US)

Baraclude (Bristol-Myers Squibb).

An analog of guanosine formulated as tablets and suspension for oral use.

Baraclude (BMS)

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.

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.

Oral absorption： 100%
C_max 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.

Treatment of chronic hepatitis B virus infection in patients >16 years of age

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.

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).

Potentially hazardous interactions with other drugs None known

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.

Store at -20°C