Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C36H56O6.2C7H17NO5 |
Molecular Weight | 975.2534 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 18 / 18 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.[H][C@]12[C@@H](CC[C@@]1(CC[C@]3(C)[C@]2([H])CC[C@]4([H])[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(O)=O)C(C)(C)[C@]5([H])CC[C@@]34C)C(O)=O)C(C)=C
InChI
InChIKey=TXIOIJSYWOLKNU-FLQODOFBSA-N
InChI=1S/C36H56O6.2C7H17NO5/c1-21(2)22-12-17-36(30(40)41)19-18-34(8)23(28(22)36)10-11-25-33(7)15-14-26(42-27(37)20-31(3,4)29(38)39)32(5,6)24(33)13-16-35(25,34)9;2*1-8-2-4(10)6(12)7(13)5(11)3-9/h22-26,28H,1,10-20H2,2-9H3,(H,38,39)(H,40,41);2*4-13H,2-3H2,1H3/t22-,23+,24-,25+,26-,28+,33-,34+,35+,36-;2*4-,5+,6+,7+/m000/s1
Molecular Formula | C7H17NO5 |
Molecular Weight | 195.2136 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 4 / 4 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
Molecular Formula | C36H56O6 |
Molecular Weight | 584.8262 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 9 / 10 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
Bevirimat (3-O-(3',3'-dimethylsuccinyl) betulinic acid or MPC-4326 or PA-457) potently inhibits replication of both WT and drug-resistant HIV-1 isolates and demonstrate that the compound acts by disrupting a late step in Gag processing involving conversion of the capsid precursor (p25) to mature capsid protein (p24). Bevirimat inhibits replication of both wild-type and drug-resistant HIV-1 isolates in vitro, achieving similar 50% inhibitory concentration values with both categories. Serial drug passage studies have identified six single amino acid substitutions that independently confer bevirimat resistance. These resistance mutations occur at or near the CA-SP1 cleavage site, which is not a known target for resistance to other antiretroviral drugs. Bevirimat has been in phase 2 trial for the treatment of HIV infections. Bevirimat has demonstrated a consistent pharmacokinetic profile in healthy volunteers and HIV-infected patients. The demonstration of an antiviral effect following a single oral dose of bevirimat validates maturation inhibition as a potential target for antiretroviral therapeutics in humans.
Originator
Sources: https://www.ncbi.nlm.nih.gov/pubmed/8176401
Curator's Comment: reference retrieved from https://www.ncbi.nlm.nih.gov/pubmed/14573704
Approval Year
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
11.9 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104 |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
BEVIRIMAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
25.1 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104 |
200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered: |
BEVIRIMAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
6 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104 |
50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered: |
BEVIRIMAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
58 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104 |
200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
BEVIRIMAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
8 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104 |
25 mg 1 times / day multiple, oral dose: 25 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
BEVIRIMAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
31.6 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104 |
100 mg 1 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
BEVIRIMAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
43.7 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104 |
150 mg 1 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
BEVIRIMAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
180.9 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104 |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
BEVIRIMAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
382.9 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104 |
200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered: |
BEVIRIMAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
88.2 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104 |
50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered: |
BEVIRIMAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
1113.7 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104 |
200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
BEVIRIMAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
156.5 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104 |
25 mg 1 times / day multiple, oral dose: 25 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
BEVIRIMAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
599.5 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104 |
100 mg 1 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
BEVIRIMAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
827.9 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104 |
150 mg 1 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
BEVIRIMAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
62.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104 |
200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
BEVIRIMAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
1.75 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104 |
25 mg 1 times / day multiple, oral dose: 25 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
BEVIRIMAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
56.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104 |
100 mg 1 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
BEVIRIMAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
61.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104 |
150 mg 1 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
BEVIRIMAT plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
no | ||||
no | ||||
Sources: https://pubmed.ncbi.nlm.nih.gov/17596104/ |
no | likely (expression study) Comment: Urinary 6β-hydroxycortisol/cortisol ratio was not influenced by Bevirimat administration. Sources: https://pubmed.ncbi.nlm.nih.gov/17596104/ |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
major [Km 13 uM] | ||||
minor [Km 6 uM] | ||||
minor | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no |
PubMed
Title | Date | PubMed |
---|---|---|
Bifunctional anti-human immunodeficiency virus type 1 small molecules with two novel mechanisms of action. | 2004 Feb |
|
Small-molecule inhibition of human immunodeficiency virus type 1 replication by specific targeting of the final step of virion maturation. | 2004 Jan |
|
Human immunodeficiency virus type 1 resistance to the small molecule maturation inhibitor 3-O-(3',3'-dimethylsuccinyl)-betulinic acid is conferred by a variety of single amino acid substitutions at the CA-SP1 cleavage site in Gag. | 2006 Dec |
|
In vitro resistance to the human immunodeficiency virus type 1 maturation inhibitor PA-457 (Bevirimat). | 2006 Nov |
|
The 3-O-(3',3'-dimethylsuccinyl) derivative of betulinic acid (DSB) inhibits the assembly of virus-like particles in HIV-1 Gag precursor-expressing cells. | 2007 |
|
Phase I and II study of the safety, virologic effect, and pharmacokinetics/pharmacodynamics of single-dose 3-o-(3',3'-dimethylsuccinyl)betulinic acid (bevirimat) against human immunodeficiency virus infection. | 2007 Oct |
Patents
Sample Use Guides
Four cohorts of six HIV-infected adults, with CD4 counts of >200 and plasma viral loads of 5,000 to 250,000 transcripts/ml and not currently receiving antiretroviral therapy, were randomized to receive a single oral dose of placebo, 75, 150, or 250 mg of bevirimat.
The study was a 10-day, randomised, double-blind, placebo-controlled, dose escalation study. A total of 48 healthy male volunteers, aged 19-54 years, took part in the study. Treatment was administered for 10 days in six escalating dose cohorts (n = 8 in each cohort; 6 bevirimat, 2 placebo). The doses of bevirimat given in each successive cohort were 25 mg, 50 mg, 75 mg (with 150 mg loading dose), 100 mg, 150 mg and 200mg. Safety follow-up was performed 28 days after the first dose.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/14573704
Bevirimat (PA-457) was shown to be a potent in vitro inhibitor of HIV-1 replication. In assays using patient-derived WT virus isolates, PA-457 exhibited a mean IC50 of 10.3 nM.
Substance Class |
Chemical
Created
by
admin
on
Edited
Fri Dec 15 17:20:52 GMT 2023
by
admin
on
Fri Dec 15 17:20:52 GMT 2023
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Record UNII |
O6DDV91W1M
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Record Status |
Validated (UNII)
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Record Version |
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-
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NCI_THESAURUS |
C1660
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11400413
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823821-85-8
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CHEMBL404519
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C78045
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O6DDV91W1M
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300000044585
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65484
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RR-125
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m2466
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PRIMARY | Merck Index |
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PARENT -> SALT/SOLVATE |
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ACTIVE MOIETY |