153611-19-9

Basic information

• Product Name: AMDOXOVIR
• Synonyms: AMDOXOVIR
• CAS NO: 153611-19-9
• Molecular Weight: 0
• Mol File: 153611-19-9.mol
• Article Data: 11

Chemical Properties

• Appearance: /
• CAS DataBase Reference: AMDOXOVIR(CAS DataBase Reference)
• NIST Chemistry Reference: AMDOXOVIR(153611-19-9)
• EPA Substance Registry System: AMDOXOVIR(153611-19-9)

Safety Data

• Hazardous Substances Data: 153611-19-9(Hazardous Substances Data)

Usage

Description

Amdoxovir, also known as DAPD, AMDX, or ()-b-D-2,6-diaminopurine dioxolane, is a novel nucleoside analog reverse transcriptase (NRTI) inhibitor drug. It is specifically designed for the treatment of human immunodeficiency virus (HIV) type 1 infections. Amdoxovir functions as a prodrug of the purine nucleoside analog ()-b-D-dioxolane guanosine (DXG). Once administered, Amdoxovir is rapidly deaminated in vivo by adenosine deaminase to its active metabolite, DXG. This active form, DXG, is then phosphorylated to DXG triphosphate, which acts as an inhibitor of HIV reverse transcriptase (RT). Both Amdoxovir and DXG are dioxolane derivatives of the nucleoside guanine, featuring an oxygen atom at the 3u position of the sugar moiety.

Uses

Used in Pharmaceutical Industry:
Amdoxovir is used as an antiviral agent for the treatment of HIV-1 infections. It serves as a reverse transcriptase inhibitor, preventing the replication of the virus within the host cells and thus helping to manage the progression of the disease.
Additionally, Amdoxovir is used in the treatment of hepatitis B infections. As a reverse transcriptase inhibitor, it helps control the viral load and reduces the risk of liver damage and complications associated with chronic hepatitis B infection.

Mechanism of action

Despite being significantly more potent than amdoxovir, DXG has poor oral bioavailability. Therefore, amdoxovir was synthesized as its prodrug. Amdoxovir is rapidly converted in vivo and in vitro to DXG by the action of adenosine deaminase (ADA), which hydrolyzes the 6-amino group of amdoxovir. In a study by Furman et al. (2001), in the presence of calf ADA, 50% of the concentration of amdoxovir in whole human blood was converted to DXG in 2.4 hours . Oral administration of amdoxovir to cynomolgus monkeys showed that the plasma concentrations of DXG were significantly higher than the plasma concentrations of amdoxovir. This confirmed that amdoxovir is rapidly converted to DXG in vivo, and is a prodrug of DXG. Multiple human pharmacologic studies have also shown that oral amdoxovir is rapidly converted to DXG in humans. Like all NRTIs, DXG is itself a prodrug and must be converted to the triphosphate for it to be active; DXG-TP is an analog of 2u-deoxyguanosine, which is normally incorporated into HIV DNA during its synthesis by HIV RT. DXG, like many other nucleoside analogs, is converted to its 5u-triphosphate derivative by cellular kinases. Following this conversion, DXG-TP inhibits HIV-1 RT with a Ki of 0.019 mM. In contrast, as mentioned above, the Ki for amdoxovirTP is 250 mM, indicating that DXG is the more potent of the two compounds. DXG-TP inhibits the HIV RT by two mechanisms. DXG-TP competes with the natural substrate 2u-deoxyguanosine-TP for incorporation into newly formed DNA, reversibly inhibiting the RT. Once DXG-TP is incorporated, it results in DNA chain termination because DXG-TP lacks a hydroxyl moiety that is needed to form a 3u–5u phosphodiester bond with the next nucleoside. The complex of the terminated DNA chain with RT is irreversible.

Clinical Use

In early studies, dioxolane nucleoside derivatives showed potent anti-HIV activity in vitro. DXG has poor solubility and low oral bioavailability; amdoxovir, a more bioavailable prodrug, was developed initially at Triangle Pharmaceuticals and development is now continuing at RFS Pharma LLC. In vitro, DXG has potent antiviral activity against wild-type HIV-1, and, more significantly, against clinical isolates of HIV-1 which are resistant to current NRTIs. DXG also has in vitro activity against HIV2 and hepatitis B viruses, but the drug is not being developed for these indications. Amdoxovir has undergone three phase I and four phase I/ II trials for treatment of HIV-1. Amdoxovir is formulated as 300- or 500-mg capsules for oral administration.

Drug interactions

Amdoxovir has been administered to humans in combination with mycophenolate mofetil, enfuvirtide (T-20, fusion inhibitor), and zidovudine. Pharmacokinetic studies have been performed only with zidovudine. No drug interactions were identified for either zidovudine or amdoxovir in relationship to the plasma concentrations of ZDV or DXG . This was not unexpected given the different phosphorylating pathways of these two drugs. No drug interaction studies were reported for the mycophenolate mofetil study. No clinical data on the other guanosine analog, abacavir, are available. However, nucleotide competition studies conducted in tissue-cultured cells indicate no competitive inhibition of carbovir triphosphate, the active metabolite of abacavir. Additionally, abacavir did not interfere with the phosphorylation of DXG. Since abacavir uses a different phosphorylation pathway to produce carbovir triphosphate, amdoxovir and abacavir could be administered together.

Upstream product

• 5451-40-1 2,6 dichloropurine 
• 75788-35-1 9-Trimethylsilyl-2,6-dichlorpurin 
• 1904-98-9 2,6-diaminopurine 
• 108436-98-2 C₁₄H₃₀N₆Si₃ 
• 1904-98-9 2,6-diaminopurine 
• 145513-99-1 (-)-β-D-2-amino-6-chloropurine dioxolane 
• 145440-02-4 (-)-(2R,4R)-2-amino-9-<2-<<(tert-butyldiphenylsilyl)oxy>methyl>-1,3-dioxolan-4-yl>-6-chloropurine 
• 855520-14-8 4-methoxybenzoic acid 4(R)-(2,6-dichloro-purin-9-yl)-[1,3]-dioxolan-2(R)-yl-methyl ester 
• 855520-10-4 isobutyric acid 4(R)-(2,6-dichloro-purin-9-yl)-[1,3]-dioxolan-2(R)-yl-methyl ester 
• 855520-15-9 4-methoxybenzoic acid 4(R)-(2,6-diamino-purin-9-yl)-[1,3]-dioxolan-2(R)-yl-methyl ester 
• 838845-03-7 isobutyric acid 4(R)-(2,6-diamino-purin-9-yl)-[1,3]-dioxolan-2(R)-yl-methyl ester 
• 145440-11-5 9-[(2R,4R)-2-(tert-Butyl-diphenyl-silanyloxymethyl)-[1,3]dioxolan-4-yl]-9H-purine-2,6-diamine 

Downstream Products

• 1239439-31-6 (2S)-ethyl 2-(((((2R,4R)-4-(2-amino-6-hydroxy-9H-purin-9-yl)-1,3-dioxolan-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate 

Relevant articles and documents

MONOPHOSPHATE PRODRUGS OF DAPD AND ANALOGS THEREOF

The present invention is directed to compounds, compositions and methods for treating or preventing cancer and viral infections, in particular, HIV and HBV, in human patients or other animal hosts. The compounds are certain 6-substituted-2-amino-purine di

Methods to manufacture 1,3-dioxolane nucleosides

This application provides a process for preparing enantiomerically pure β-D-dioxolane nucleosides. In particular, a new synthesis of (?)-DAPD, suitable for large scale development, is described. In one embodiment the invention provides a process for prepa

Stereoselective synthesis of nucleoside analogues

The invention is a process for stereoselectively producing a dioxolane nucleoside analogue from an anomeric mixture of β and α anomers represented by the following formula A or formula B: wherein R is selected from the group consisting of C1-6alkyl and C6-15aryl and Bz is benzoyl. The process comprises hydrolyzing said mixture with an enzyme selected from the group consisting of Protease N, Alcalase, Savinase, ChiroCLEC-BL, PS-30, and ChiroCLEC-PC to stereoselectively hydrolyze predominantly one anomer to form a product wherein R1is replaced with H. The process also includes the step of separating the product from unhydrolyzed starting material. Additionally, the functional group at the C4 position is stereoselectively replaced with a purinyl or pyrimidinyl or derivative thereof.