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Entecavir structure

Entecavir

Entecavir is a cyclopentyl guanosine analog launched for the once-dailyoral treatment of chronic hepatitis B virus (HBV) infection, and it is the thirdnucleoside or nucleotide analog to be marketed for this indication. Lamivudine, adeoxythiacytosine analog, and adefovir dipivoxil, a nucleotide analog, have beenmarketed since 1998 and 2002, respectively. Entecavir and adefovir are specificallyindicated for HBV, whereas lamivudine is indicated for both HBV and HIV infections.In mammalian cells, entecavir is efficiently phosphorylated to the activetriphosphate form, which competes with the natural substrate deoxyguanosinetriphosphate and functionally inhibits all three activities of the HBV polymerase:(1) base priming, (2) reverse transcription of the negative strand from the pregenomicmessenger RNA, and (3) synthesis of the positive strand of HBV DNA.The most common adverse events associated withthe use of entecavir are similar to those typically seen with HBV therapy andinclude headache, abdominal pain, diarrhea, fatigue, and dizziness. View more+
 
1. Names and Identifiers
1.1 Name
Entecavir
1.2 Synonyms
(1S,3R,4S)-9-[4-Hydroxy-3-(hydroxyMethyl)-2-Methylenecyclopentyl]guanine; 2-Amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one; 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylidenecyclopentyl]-1,9-dihydro-6H-purin-6-one; 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylidenecyclopentyl]-3H-purin-6-one; 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylidenecyclopentyl]-9H-purin-6-ol; 6H-Purin-6-one, 2-amino-1,9-dihydro-9-((1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl)-; 6H-Purin-6-one, 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-; 9H-purin-6-ol, 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-; Aids098045; Aids-098045; Baraclude; entecavir (anhydrous); Entecavir USP Impurity B; Enticavir; EntikaweiPian; Etv; UNII-NNU2O4609D;
1.3 CAS No.
142217-69-4
1.4 CID
135398508
1.5 EINECS
604-279-5
1.6 Molecular Formula
C12H15N5O3
1.7 Inchi
InChI=1S/C12H15N5O3/c1-5-6(3-18)8(19)2-7(5)17-4-14-9-10(17)15-12(13)16-11(9)20/h4,6-8,18-19H,1-3H2,(H3,13,15,16,20)/t6-,7-,8-/m0/s1
1.8 InChkey
QDGZDCVAUDNJFG-FXQIFTODSA-N
1.9 Canonical Smiles
C=C1C(CC(C1CO)O)N2C=NC3=C2N=C(NC3=O)N
1.10 Isomers Smiles
C=C1[C@H](C[C@@H]([C@H]1CO)O)N2C=NC3=C2N=C(NC3=O)N
2. Properties
2.1 Solubility
In water, 2.4X10+3 mg/L, temp not specified
2.2 Appearance
white to off-white/yellow crystalline powder
2.3 Storage
-20°C Freezer
2.4 Chemical Properties
White to Off-White/Yellow Crystalline Powder
2.5 Color/Form
White to off white powder
2.6 PH
pH = 7.9 in a saturated solution of water; at 25 deg C
2.7 Physical
Solid
2.8 pKa
14.22±0.60(Predicted)
2.9 Water Solubility
In water, 2.4X10+3 mg/L, temp not specified
2.10 StorageTemp
-20°C
3. Use and Manufacturing
3.1 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.
3.2 Description
White to Off-White/Yellow Crystalline PowderChEBI: 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 transcriptas
3.3 Methods of Manufacturing
Preparation: R. Zahler, W. A. Slusarchyk, European Patent Office 481754; eidem, United States of America patent 5206244 (1992, 1993 both to Squibb)
3.4 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
4. Safety and Handling
4.1 Exposure Standards and Regulations
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl entecavir, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
4.2 Octanol/Water Partition Coefficient
log Kow = -0.49 (est)
4.3 DisposalMethods
SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.
4.4 Formulations/Preparations
0.05 mg/mL (Rx) Baraclude (citric acid, maltitol, methylparaben, orange flavor, sodium citrate) /Oral solution/
0.5 mg /tablet/ (Rx) Baraclude (crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, polysorbate 80, povidone, titanium dioxide).
1 mg /tablet/ (Rx) Baraclude (crospovidone, hypromellose, iron oxide red, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, povidone, titanium dioxide).
5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

no data available

2.2 GHS label elements, including precautionary statements

Pictogram(s) no data available
Signal word

no data available

Hazard statement(s)

no data available

Precautionary statement(s)
Prevention

no data available

Response

no data available

Storage

no data available

Disposal

no data available

2.3 Other hazards which do not result in classification

no data available

6. NMR Spectrum
7. Synthesis Route
142217-69-4Total: 55 Synthesis Route
 
4984-82-1
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142217-69-4
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8. Precursor and Product
precursor:
9. Computed Properties
10.Other Information
Hepatitis B treatment first-line drug
Entecavir is a new generation of guanine nucleoside analogues oral medicine for treatment of hepatitis B virus infection in, mainly for the treatment of adult patients with viral replication activity and serum transaminase continued to increase, or liver tissue for pathological activity of chronic hepatitis B, is currently down virus the fastest and the most powerful, the mutation rate lowest nucleoside analogues.
Data show that different in patients with chronic hepatitis B, including nucleoside naive and nucleoside treated and liver cirrhosis patients, using well entecavir tablets in the treatment can control the disease rapidly and easily reach the treatment of reality end, namely the hepatitis B virus unmeasured; through adherence to treatment, a considerable portion of patients can be arrived at the end of treatment satisfaction, namely e antigen serology conversion, some patients can even reach the ideal for the treatment of end, namely surface antigen negative.
Side Effects
In the treatment of hepatitis B, entecavir as first-line antiviral drugs in the treatment of hepatitis B virus on the effect is worthy of recognition, have a significant treatment effect of serum transaminase ALT increased or liver lesions for active viral replication in patients with chronic hepatitis B in adults,. However, the clinical application of entecavir is affected due to the side effects of entecavir. 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. In trials with lamivudine controls, the incidence of adverse events is equivalent to lamivudine.
According to the study, 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. In these studies, using entecavir of the patients in the treatment process, ALT increased to 10 times of the normal value upper limit and baseline values of 2 times, the generally continue to medication for a period of time, the ALT returned to normal; prior to or concurrently with viral load 2 on the numerical decline. So during the treatment, regular liver function should be tested.
In the side effects of entecavir, most not easy to accept the resistance for patients, resistance will increase the difficulty of treatment, medication time to grow, for patients, psychological pressure and economic pressure will increase, half-way stopping may cause illness rebound. Although existing nucleoside analogues inhibited viral force of entecavir is strong, and mutation rate is lowest (newly diagnosed 4 years less than 1%), but the price is also the most expensive, more suitable for economic conditions, long-term treatment.
Because of the side effects of entecavir, patients with hepatitis B should be taken entecavir under the guidance of specialized subject doctor, once appear uncomfortable to reflect to the doctor. In the necessary condition, timely adjustment of treatment. And the use entecavir therapy does not reduce hepatitis B through sexual contact or blood transmission of hepatitis B virus risk. Therefore, it is necessary to take appropriate protective measures.
usage and dosage
Patients with chronic hepatitis B should be under the guidance of experienced doctors taking this product. Recommended dosage: adult and over the age of 16 young oral this product, once a day, each 0.5 mg. lamivudine treatment viremia or patients with lamivudine resistant mutants to once a day, each 1.0 mg (0.5mg two pieces), taken on an empty stomach (a meal or a meal after at least 2 hours).
Genotoxicity
In the study of reproductive toxicity, in 4 consecutive weeks of entecavir, dose up to 30mg/kg, the dosage of 90 times more than the recommended dose of 1.0mg/ day, the highest body did not find the fertility of male and female rats affected. In toxicology of entecavir studies, when dose is 35 times of body dose or more, found the dog rodent animal appeared degenerative changes. The vas deferens in the monkey experiments, no changes were found in testis. Study on reproductive toxicity in rats and rabbits, the oral dose of 200 and 13mg/kg/ day, which is equivalent to 28 times of the highest dose 1.0mg/ day (in rats) and 212 times (for rabbit), no embryo and maternal toxicity. In rabbits, the dosage of female rabbits is 883 times the daily dose of 1.0mg/ in the human body, the observed toxic effects on embryo fetal rabbit (absorption), reduce the level of ossification (tongue Bone), and the 13th rib occurrence rate increased. In the practical before birth and after birth of rats oral clinical trials converted that card quantity is greater than 94 times of people 1.0mg/ a daily dose, having not to impact on future generations. Entecavir can be from rat milk secretion.
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.
Brand name
Baraclude (Bristol-Myers Squibb).
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)
Pharmaceutical Applications
An analog of guanosine formulated as tablets and suspension for oral use.
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.
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
Severity of adverse reactions was comparable to that of lamivudine, with headache, fatigue, upper respiratory infections and abdominal pain being most common. Lactic acidosis and hepatic steatosis were rarely observed.
Chemical 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).

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