Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C44H58N8O6 |
| Molecular Weight | 794.9813 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 6 / 6 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CC(C)[C@H](NC(=O)N(C)CC1=CC=CC=N1)C(=O)N[C@@H](CC2=CC=CC=C2)[C@@H](O)[C@@H](O)[C@H](CC3=CC=CC=C3)NC(=O)[C@@H](NC(=O)N(C)CC4=NC=CC=C4)C(C)C
InChI
InChIKey=QPVWMQXBTCSLCB-BYAJYZPISA-N
InChI=1S/C44H58N8O6/c1-29(2)37(49-43(57)51(5)27-33-21-13-15-23-45-33)41(55)47-35(25-31-17-9-7-10-18-31)39(53)40(54)36(26-32-19-11-8-12-20-32)48-42(56)38(30(3)4)50-44(58)52(6)28-34-22-14-16-24-46-34/h7-24,29-30,35-40,53-54H,25-28H2,1-6H3,(H,47,55)(H,48,56)(H,49,57)(H,50,58)/t35-,36-,37-,38-,39-,40+/m0/s1
A-77003 is an HIV-1 protease inhibitor, which was developed by Abbott for the treatment of patients with HIV infection. The drug demonstrated good potency in vitro and was tested in phase I clinical trial. However, the development was terminated as A-77003 as formulated for use in the phase I study was shown to be unsuitable for clinical use.
Originator
Approval Year
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
0.358 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7492104/ |
0.28 mg/kg/h 24 times / day multiple, intravenous dose: 0.28 mg/kg/h route of administration: Intravenous experiment type: MULTIPLE co-administered: |
A-77003 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
0.143 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7492104/ |
0.07 mg/kg/h 24 times / day multiple, intravenous dose: 0.07 mg/kg/h route of administration: Intravenous experiment type: MULTIPLE co-administered: |
A-77003 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
0.174 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7492104/ |
0.14 mg/kg/h 24 times / day multiple, intravenous dose: 0.14 mg/kg/h route of administration: Intravenous experiment type: MULTIPLE co-administered: |
A-77003 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
20 min EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7492104/ |
0.28 mg/kg/h 24 times / day multiple, intravenous dose: 0.28 mg/kg/h route of administration: Intravenous experiment type: MULTIPLE co-administered: |
A-77003 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
Doses
| Dose | Population | Adverse events |
|---|---|---|
0.28 mg/kg multiple, intravenous Highest studied dose Dose: 0.28 mg/kg Route: intravenous Route: multiple Dose: 0.28 mg/kg Sources: |
unhealthy Health Status: unhealthy Sex: M+F Food Status: UNKNOWN Sources: |
Other AEs: Phlebitis, headache... |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Fatigue | 0.28 mg/kg multiple, intravenous Highest studied dose Dose: 0.28 mg/kg Route: intravenous Route: multiple Dose: 0.28 mg/kg Sources: |
unhealthy Health Status: unhealthy Sex: M+F Food Status: UNKNOWN Sources: |
|
| headache | 0.28 mg/kg multiple, intravenous Highest studied dose Dose: 0.28 mg/kg Route: intravenous Route: multiple Dose: 0.28 mg/kg Sources: |
unhealthy Health Status: unhealthy Sex: M+F Food Status: UNKNOWN Sources: |
|
| Phlebitis | 9 patients | 0.28 mg/kg multiple, intravenous Highest studied dose Dose: 0.28 mg/kg Route: intravenous Route: multiple Dose: 0.28 mg/kg Sources: |
unhealthy Health Status: unhealthy Sex: M+F Food Status: UNKNOWN Sources: |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Escape mutants of HIV-1 proteinase: enzymic efficiency and susceptibility to inhibition. | 1997-04-25 |
|
| Design, synthesis, and resistance patterns of MP-134 and MP-167, two novel inhibitors of HIV type 1 protease. | 1996-01-01 |
|
| Efficacy of constant infusion of A-77003, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, in limiting acute HIV-1 infection in vitro. | 1995-11 |
|
| Kinetic characterization and cross-resistance patterns of HIV-1 protease mutants selected under drug pressure. | 1995-07-25 |
|
| Characterization of a human immunodeficiency virus type 1 variant with reduced sensitivity to an aminodiol protease inhibitor. | 1995-04 |
|
| Antiviral properties of aminodiol inhibitors against human immunodeficiency virus and protease. | 1995-02 |
|
| Aminodiol HIV protease inhibitors. 1. Design, synthesis, and preliminary SAR. | 1994-06-10 |
|
| Selection of multiple human immunodeficiency virus type 1 variants that encode viral proteases with decreased sensitivity to an inhibitor of the viral protease. | 1994-06-07 |
|
| A C2 symmetry-based HIV protease inhibitor, A77003, irreversibly inhibits infectivity of HIV-1 in vitro. | 1994-06 |
|
| Characterization of human immunodeficiency virus type 1 variants with increased resistance to a C2-symmetric protease inhibitor. | 1994-03 |
|
| Symmetry-based inhibitors of HIV protease. Structure-activity studies of acylated 2,4-diamino-1,5-diphenyl-3-hydroxypentane and 2,5-diamino-1,6-diphenylhexane-3,4-diol. | 1993-02-05 |
|
| In vitro inhibition of human immunodeficiency virus (HIV) type 1 replication by C2 symmetry-based HIV protease inhibitors as single agents or in combinations. | 1992-05 |
|
| Antiviral and pharmacokinetic properties of C2 symmetric inhibitors of the human immunodeficiency virus type 1 protease. | 1991-11 |
Patents
Sample Use Guides
In a clinical trial, patients were given A-77003 as by continuous intravenous infusion at dosages of 0.035, 0.07, 0.14, and 0.28 mg/kg of body weight per h. The drug was given first for 24 h and then for up to an additional 4 weeks in a second infusion period following at least a 6-day washout.
Route of Administration:
Intravenous
In studies of acute HIV infection, 2.5 x 10(3) H9, CEM, or U937 cells per well were preincubated in 200 ul of serum-free RPMI 1640 medium in 96-well plates for 4 h with 0, 0.001, 0.01, 0.1, 1, 10, 25, 50, and 100 uM of A-77003 prior to infection. Cells were infected with 25 U of infectious HIV, and 2h postinfection cells were washed 3 times with medium and resuspended in medium containing the same concentrations of drugs as prior to infection plus 10% fetal calf serum.
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ACTIVE MOIETY
