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Entecavir
- Iupac Name：2-amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylidenecyclopentyl]-3H-purin-6-one
- CAS No.: 142217-69-4
- Molecular Weight：277.284
- Modify Date.: 2022-10-30 18:36
- Introduction: 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.
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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
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- 1.3 CAS No.
- 142217-69-4
- 1.4 CID
- 135398508
- 1.5 EINECS(EC#)
- 604-279-5
- 1.6 Molecular Formula
- C12H15N5O3 (isomer)
- 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 InChIkey
- 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 Density
- 1.81
- 2.1 Melting point
- 249-252°C
- 2.1 Boiling point
- 734.2 °C at 760 mmHg
- 2.1 Refractive index
- 1.837
- 2.1 Flash Point
- 397.9 °C
- 2.1 Precise Quality
- 277.11700
- 2.1 PSA
- 130.05000
- 2.1 logP
- -0.24660
- 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 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)
- 3.3 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 Safety Statements
- 24/25
- 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 RIDADR
- NONH for all modes of transport
- 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).
- 4.5 WGK Germany
- 3
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
7. Synthesis Route
142217-69-4Total: 55 Synthesis Route
9. Other Information
- 9.0 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.
- 9.1 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. - View all
- 9.2 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).
- 9.3 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.
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- 9.4 Chemical Properties
- White to Off-White/Yellow Crystalline Powder
- 9.5 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
- 9.6 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.
- 9.7 Brand name
- Baraclude (Bristol-Myers Squibb).
- 9.8 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.
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- 9.9 Originator
- BMS (US)
- 9.10 Pharmaceutical Applications
- An analog of guanosine formulated as tablets and suspension for oral use.
- 9.11 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.
- 9.12 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.
- 9.13 Clinical Use
- Treatment of chronic hepatitis B virus infection in patients >16 years of age
- 9.14 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.
- 9.15 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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10. Computational chemical data
- Molecular Weight: 277.284g/mol
- Molecular Formula: C12H15N5O3
- Compound Is Canonicalized: True
- XLogP3-AA: -1.3
- Exact Mass: 277.11748936
- Monoisotopic Mass: 277.11748936
- Complexity: 480
- Rotatable Bond Count: 2
- Hydrogen Bond Donor Count: 4
- Hydrogen Bond Acceptor Count: 5
- Topological Polar Surface Area: 126
- Heavy Atom Count: 20
- Defined Atom Stereocenter Count: 3
- Undefined Atom Stereocenter Count: 0
- Defined Bond Stereocenter Count: 0
- Undefined Bond Stereocenter Count: 0
- Isotope Atom Count: 0
- Covalently-Bonded Unit Count: 1
- CACTVS Substructure Key Fingerprint: AAADccBzsAAAAAAAAAAAAAAAAAAAAeIAAAAgAAAAAAAAAEABgAAAHgAQCAAADTzhlgYFsBfMEgCoAwdzdACAgC03EKABUAGoVEiAWApAySAUQIgPwQLAAGGwUAMOAAAAAAAAAAAAAAAAAAAAACEABAAAAA==
11. Question & Answer
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Although Entecavir is effective, there are certain groups of people who should not use it. Currently, Entecavir is the most common drug used in clinical treatment of hepatitis B. This medication has m..
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Antiviral therapy is an important means of treating hepatitis B, and nucleoside antiviral drugs are the main treatment drugs. These drugs include lamivudine, telbivudine, Entecavir, adefovir dipivoxil..
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Entecavir (ETV) is an oral prescription antiviral medication used to treat liver infections caused by the hepatitis B virus. While it will not cure the virus, it can prevent it from replicating and ca..
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General Description Entecavir is a highly effective antiviral drug used to treat chronic hepatitis B (CHB) infection. It inhibits viral replication through its active form, Entecavir-triphosphate. Wit..
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