Entecavir Monohydrate for Chronic Adult Hepatitis B

English name：Entecavir hydrate
CAS number：209216-23-9
Chinese synonym:
ENTECAVIRMONOHYDRATE Entecavir; Entecavir control article; Entecavir 100MG; Entecavir monohydrate, nucleoside analog, Can inhibit reverse transcription; Entecavir monohydrate standard; 2-amino-9- [(1S, 3R, 4S) -4-hydroxy-3-hydroxymethyl-2-methylene cyclentyl] -1, 9-dihydrogen-6H-Chemicalbook purine-6-ketone monohydrate; 2-amino-9- [(1S, 3R, 4S) -4-hydroxy-3-hydroxymethyl-2-mevalylene] -1, 9-hydrogen-6-H-purine-6-ketone hydrohydrate; 2-amino-9- [(1S, 3R, 4S) -4-hydroxy-3-hydroxymethyl-2-mevalylene] -1, 9-hydrogen-6-H-purine-6-ketomonohydrate
English synonym:
entecavirhydrate;ENTECAVIRMONOHYDRATE;2-Amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-onemonohydrate;Entecavirhydrate/2-Amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-onemonohydrate;2-Amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxyChemicalbook-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-onemonohydrate,99.9%;2-Amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-onemonohydrate,99.7%;EntecavirMonohydrateIsoMers;2-aMino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxyMethyl)-2-Methylidenecyclopentyl]-6,9-dihydro-3H-purin-6-one
Molecular formula：C12H17N5O4
Molecular weight：295.3
EINECS Number: 606-668-5
Related category:
Research reagents; antiviral products; nucleosides; intermediates; antiviral drugs; raw materials; active pharmaceutical ingredients; medical raw materials; pharmaceutical chemistry; antiviral; pharmaceutical raw materials; API; BaracluChemicalbookde; LiverDiseaseSeries; pharmaceutical active ingredients; pharmaceutical, pesticide, and dye intermediates; organic chemistry; chemical intermediates; daily chemicals; medicine; chemical reagents
The Mol file: 209216-23-9.mol
 

Structural formula:

Chemical properties of Entecavir monohydrate

Melting point: >220°

Specific rotation: D +35.0° (c = 0.38 in water)

Density: 1.81

Storage conditions: Keep in dark place,Sealed in dry,Store in freezer, under -20°C

Solubility: DMSO (Slightly), Methanol (Sparingly), Water (Slightly, Heated, Sonicated)

Form: Solid

Color: White to Off-White

Merck: 14,3595

InChI: InChI=1/C12H15N5O3.H2O/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, 17-19 h, 1-3 h2, (H3, 13,15,16,20); 1H2/t6-,7-,8-; /s3

InChIKey: YXPVEXCTPGULBZ-UQHDSAJHNA-N

SMILES: C = C1 @ @ H [C] (@ @ H [C] (O) C @ @ H [C] 1 n1c = NC2C (NC (N) = NC1 = 2) = O) CO., O | & 1:2, 3, 6, r |

CAS database: 209216-23-9 (CAS DataBase Reference)

Antiviral drug

Entecavir monohydrate is a novel cyclovaleryl guanosine anti-hepatitis B drug with pharmacological effects similar to Entecavir. It is clinically suitable for the treatment of chronic hepatitis B in adults with active viral replication, persistent elevated serum aminotransferase ALT or active liver lesions. This product is a guanine nucleoside analogue and has an inhibitory effect on hepatitis B virus (HBV) polymerase. It can be phosphorylated into an active triphosphate, which has a half-life of 15 hours in the cell. By competing with deoxyguanosine triphosphate, a natural substrate of HBV polymerase, Entecavir triphosphate inhibits all three activities of viral polymerase (reverse transcriptase) :

(1) Initiation of HBV polymerase.

(2) Formation of pre-genomic mRNA reverse transcriptional negative chains.

(3) Synthesis of positive strand of HBVDNA.

The inhibitory constant (Ki) of Entecavir triphosphate on HBVDNA polymerase was 0.0012μm. Entecavir triphosphate had weak inhibitory effects on α, β, δDNA polymerase and mitochondrial γDNA polymerase, with Ki values ranging from 18 to 160μm.

Antiviral activity

In human HepG2 cells transfected with wild-type HBV, the concentration required for Entecavir to inhibit 50% viral DNA synthesis (EC50) was 0.004μm. The median EC50 of Entecavir for lamivudine-resistant virus strains (rtL180M, rtM204V) was 0.026μm(range 0.01 to 0.059μm). Entecavir showed no clinically relevant activity against human immunodeficiency virus type 1 (HIV) grown in cell culture (EC50>10μmChemicalbook). Daily or weekly use of this product reduces hepatitis virus DNA levels in North American groundhogs and ducks. A long-term study of five North American marmots showed that oral administration of 0.5mg/kg of entecavir per week (equivalent to a human dose of 1.0mg) kept viral DNA at undetectable levels in three of them

Drug resistance

In vitro studies: In cell tests, lamivudine-resistant virus strains were found to be 8 to 30 times less dominant sensitive to entecavir. If the hepatitis B virus polymerase is inherently lamivudine-resistant to amino acid substitution (rtL180M and/or rtM204V/I), coupled with a substitution mutation at rtT184, rtS202, or rtM250, or in combination with or without a substitution mutation at rtI169, Both resulted in an even greater (> 70-fold) reduction in manifest sensitivity to entecavir. Cross resistance: Cross resistance has been found in nucleoside analogized drugs against Chemicalbook HBV, and Entecavir was found in cell tests to be 8 to 30 times less inhibitory against lamivudine-resistant (rtL180M and/or rtM204V/I) strains than wild strains. Entecavir is also fully sensitive to recombinant viruses with adefovir resistance variants (HBVDNA polymerase rtN236T or rtA181V variants). In vitro tests showed that virus strains isolated from patients in whom both lamivudine and Entecavir had failed were sensitive to adefovir, but remained resistant to lamivudine.

Pharmacokinetics

Absorption: After oral administration in healthy people, this product is rapidly absorbed, reaching peak concentration (Cmax) in 0.5 to 1.5 hours. The drug is administered once a day, and stable state can be reached after 6 to 10 days, and the cumulative amount is about twice. Effects of food on oral absorption: Taking 0.5mg of this product orally with a standard high-fat or low-fat meal resulted in a slight delay in drug absorption (from 0.75 hours to 1.0-1.5 hours), a 44%-46% reduction in Cmax, and an 18%-20% reduction in area under the curve (AUC). Therefore, this product should be taken on an empty stomach (at least 2 hours before or after a meal). Distribution: Pharmacokinetic data indicate that the apparent volume of distribution exceeds the total body fluid volume, indicating that this product is widely distributed in various tissues. In vitro experiments showed that the binding rate of this product to human plasma protein was 13%. Metabolism and elimination: No oxidation or acetylation metabolites of Chemicalbook were observed after administration of 14C-labeled Entecavir in humans and rats, but small amounts of phase II metabolites glucuronide conjugates and sulfuric acid conjugates were observed. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450(CYP450) enzyme system. After reaching the peak plasma concentration, the plasma concentration decreases in a double exponential manner, and the terminal clearance half-life takes about 128-149 hours. The drug accumulation index is about 2 times the dose given once a day, which indicates an effective cumulative half-life of about 24 hours. This product is mainly cleared by the kidney in its original form, and the clearance rate is 62% to 73% of the dosage. Renal clearance ranges from 360 to 471mL/min and is dose-independent, suggesting Entecavir is secreted by both glomerular filtration and reticular tubules.

Clinical evaluation

1. Entecavir has a strong antiviral ability, a low incidence of long-term drug resistance, and may have a direct inhibitory effect on cccDNA in hepatocytes. Entecavir can effectively treat chronic hepatitis B, and the efficacy is better than lamivudine.

2. The incidence of drug resistance of Entecavir was 0 in initial treatment, but 5.8% in patients with YMDD mutation.

3. Entecavir is 8 to 30 times less effective against lamivudine-resistant (rtLChemicalbook180M and/or rtM204V/I) strains than wild strains, so the therapeutic dose for lamivudine-resistant patients should be increased to 1.0mg. Entecavir is sensitive to viruses with adefovir resistance variants (HBVDNA polymerase rtN236T or rtA181V variants). Strains resistant to Entecavir are sensitive to adefovir, but remain resistant to lamivudine.

Adverse reactions and precautions

In clinical trials conducted in China, the most common adverse reactions were: elevated ALT, fatigue, dizziness, nausea, abdominal pain, abdominal discomfort, epigastric pain, liver discomfort, myalgia, insomnia, and rubella. Most of these adverse reactions were mild to moderate.

Security information

Safety description: 24 / 25

Customs code: 29339900

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