Nucleoside (acid) drugs such as lamivudine (LAM), adefovir (ADV), entecavir (ETV), and telbivudine (LDT) have been widely used in the treatment of chronic hepatitis B (CHB). These drugs can effectively inhibit the replication of hepatitis B virus (HBV), reduce viral load, restore liver function, improve liver tissue inflammation and necrosis, thereby effectively preventing or reducing the occurrence and development of liver cirrhosis and liver cancer. However, the issue of resistance to nucleoside (acid) drugs is also becoming increasingly prominent. People are looking forward to the emergence of new drugs with strong anti hepatitis B virus (HBV) efficacy and low resistance rate, in order to better serve clinical practice.
Tenofovir fumarate is a nucleotide based antiviral drug developed and marketed by Gilead Corporation in the United States. It was approved by the US FDA in 2001 for the treatment of human immunodeficiency virus (HIV) infections. In 2002, it was listed in the European Union and approved for the treatment of HIV-1 and chronic hepatitis B. Tenofovir fumarate, as a nucleotide reverse transcriptase inhibitor, is an orally available cyclic nucleotide phosphate prodrug that rapidly transforms into tenofovir after oral absorption and exerts efficacy. Due to its high bioavailability, precise efficacy, and good tolerance, TDF has become the recommended first-line anti HIV drug with the highest sales volume. The patent literature reports the synthesis method of tenofovir fumarate ester, but there are problems such as high impurities in some intermediates, low optical purity, difficult operation, low yield, substandard fumarate content, and unsuitable for industrial production.
Pharmacological effects [3]
Tenofovir axetil is a bisisopropyloxymethyl fumarate of tenofovir, which is an ester precursor of tenofovir. It is an acyclic 5 '- monophosphate adenosine analogue with broad-spectrum antiviral effects, and can inhibit the reverse transcriptase and HBV polymerase of HIV-1 and HIV-2, thereby inhibiting virus replication. After oral administration, TDF is hydrolyzed to tenofovir, which is phosphorylated by cell kinases to form a pharmacological metabolite tenofovir diphosphate. The latter competes with 5 '- triphosphate deoxyadenosine monophosphate and participates in the synthesis of viral DNA. After entering viral DNA, the lack of 3' - OH causes DNA elongation to be blocked, thereby inhibiting viral replication.
Pharmacokinetics [3]
Tenofovir is almost not absorbed by the gastrointestinal tract, so it needs to be esterified and salted to become tenofovir dipivoxil fumarate. Tenofovir dipivoxil is water-soluble and is quickly absorbed and degraded into the active substance Tenofovir after oral administration, which is then converted into the active metabolite Tenofovir bisphosphate. Within 1-2 hours after administration, tenofovir reached its peak in blood. When taken with food, the bioavailability of tenofovir can increase by approximately 40% (depending on the fat content in the diet). The intracellular half-life of tenofovir bisphosphate is approximately 10 hours and can be administered once a day. Due to the fact that the drug is not metabolized by the CYP enzyme system, the possibility of interactions with other drugs caused by this enzyme is very low. This drug mainly passes through glomerular filtration and kidney