| Stereochemistry | ABSOLUTE |
| Molecular Formula | C10H13FN2O4 |
| Molecular Weight | 244.2196 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 3 / 3 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CC1=CN([C@H]2C[C@H](F)[C@@H](CO)O2)C(=O)NC1=O
InChI
InChIKey=UXCAQJAQSWSNPQ-XLPZGREQSA-N
InChI=1S/C10H13FN2O4/c1-5-3-13(10(16)12-9(5)15)8-2-6(11)7(4-14)17-8/h3,6-8,14H,2,4H2,1H3,(H,12,15,16)/t6-,7+,8+/m0/s1
Alovudine (3’ -deoxy-3’ fluorothymidine) is a nucleoside reverse transcriptase inhibitor (NRTI) initially tested in the early 1990s, before the era of combination therapy and before the availability of plasma viral load measurement. Initial toxicity studies showed that the primary target organ of toxicity was the bone marrow. A lack of clear advantages in activity over zidovudine, the only drug approved in the early 1990s, and the potential for bone marrow toxicity caused alovudine development to be stopped [6]. However, later in vitro studies found alovudine to be very effective at suppressing several NRTI-resistant HIV-1 mutants, including isolates with multiple thymidine-associated mutations (TAMs) or multi-NRTI-resistance mutations. Alovudine at a dose of 7.5 mg/day added to a failing antiretroviral combined regimen in patients with isolates resistant to other NRTIs yielded a median viral load decline after a 4-week period in patients not receiving concomitant stavudine. In July 2003, Medivir out-licensed it's HIV antiviral MIV-310 to Boehringer Ingelheim. Under the terms of the agreement, Boehringer Ingelheim will make upfront and milestone payments to Medivir totaling up to 122 million euro in the event that all development and performance milestones are met. In March 2005, Boehringer Ingelheim recently completed a clinical trial of MIV-310 (alovudine) in HIV/AIDS. The efficacy exhibited by MIV-310 at the doses tested showed antiviral activity but did not achieve the target level of efficacy which had previously been defined. Boehringer Ingelheim, therefore, decided to stop the development of this investigational drug.
Approval Year
Overview
| CYP3A4 | CYP2C9 | CYP2D6 | hERG |
|---|---|---|---|
Drug as perpetrator
Drug as victim
Tox targets
Sourcing
PubMed
Patents
Sample Use Guides
HepG2 cells were used for activity evaluation. HepG2 cells were cultured in six-well plates at an initial concentration of 2 × 106 cells per well, and exposed to the test compounds (Alovudine) at concentrations of 0.3, 1, 3, 10, 30, 100 and 300mkM in duplicate; 0.1% DMSO and culture were used as controls. The cells were incubated at 37 ◦C under 5% CO2. The culture medium consisted of Minimal Essential Medium (MEM: Invitrogen-Gibco, Paisley, United Kingdom) supplemented with 10% fetal bovine serum albumin, sodium pyruvate (1 mM), 100,000g/ml streptomycin sulphate (Invitrogen-Gibco) and 100,000 U/ml penicillin G. The adherent cells were washed with phosphate-buffered saline (PBS) before being split by trypsinization with 1×trypsin solution (Invitrogen-Gibco) every third day. After counting the number of cells in the samples, 3 × 105 cells were taken for analysis of mitochondrial DNA. These cells were dispensed into lysis buffer (bioMerieux, Boxtel, The Netherlands) and stored at −80 ◦C prior to analysis. During counting the relative number of dead cells that remained in the culture after washing was determined by Trypan blue exclusion. The absolute number of dead cells in the adherent culture could not be determined, as the cells would have had to be trypsinized before counting, in turn necessitating thorough washing of the cells with PBS to eliminate residual proteins, which would have removed the dead cells.
ACTIVE MOIETY
