AMPRENAVIR

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C25H35N3O6S
Molecular Weight	505.627
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(C)CN(C[C@@H](O)[C@H](CC1=CC=CC=C1)NC(=O)O[C@H]2CCOC2)S(=O)(=O)C3=CC=C(N)C=C3

InChI

InChIKey=YMARZQAQMVYCKC-OEMFJLHTSA-N

InChI=1S/C25H35N3O6S/c1-18(2)15-28(35(31,32)22-10-8-20(26)9-11-22)16-24(29)23(14-19-6-4-3-5-7-19)27-25(30)34-21-12-13-33-17-21/h3-11,18,21,23-24,29H,12-17,26H2,1-2H3,(H,27,30)/t21-,23-,24+/m0/s1

HIDE SMILES / InChI

Molecular Formula	C25H35N3O6S
Molecular Weight	505.627
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	3 / 3
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21007s11,21039s10lbl.pdf
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/23519392 | https://www.ncbi.nlm.nih.gov/pubmed/11152018 | https://www.ncbi.nlm.nih.gov/pubmed/15341507

Amprenavir is an inhibitor of HIV-1 protease. Amprenavir binds to the active site of HIV-1 protease and thereby prevents the processing of viral gag and gag-pol polyprotein precursors, resulting in the formation of immature non-infectious viral particles. Amprenavir-containing combination regimens have shown virological efficacy, and have generally been well tolerated, in patients with HIV infection (primarily treatment-naive or protease inhibitor-naive). Fosamprenavir (GW433908, Lexiva, Telzir) is an oral prodrug of amprenavir, with a reduced daily pill burden. The use of protease inhibitors has also been associated with dyslipidemia and an increased risk of cardiovascular disease. Amprenavir activates Pregnane X receptor to mediate dyslipidemia.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Pregnane X receptor 35 Target ID: CHEMBL3401 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23519392	Agonist 2637	8.6 µM [EC50]
Cytochrome P450 3A 22 Target ID: CHEMBL2364675 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10952482	Inhibitor 8146	2.5 µM [IC50]
Human immunodeficiency virus type 1 protease 35 Target ID: CHEMBL243 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21007s11,21039s10lbl.pdf	Inhibitor 8146

Conditions

Condition	Modality	Targets	Highest Phase	Product
HIV-1 infection 145 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21007s11,21039s10lbl.pdf	Primary		Approved 8307	AGENERASE Approved Use AGENERASE (amprenavir) is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. Launch Date 9.2404803E11

C_max

Value	Dose	Analyte	Population
5.36 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	1200 mg 2 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
6.18 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	1200 mg single, oral dose: 1200 mg route of administration: Oral experiment type: SINGLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: HIGH-FAT
9.72 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	1200 mg single, oral dose: 1200 mg route of administration: Oral experiment type: SINGLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED
6.77 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	20 mg/kg bw 2 times / day multiple, oral dose: 20 mg/kg bw route of administration: Oral experiment type: MULTIPLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: UNHEALTHY age: CHILD sex: UNKNOWN food status: UNKNOWN
3.99 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	15 mg/kg bw 3 times / day multiple, oral dose: 15 mg/kg bw route of administration: Oral experiment type: MULTIPLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: UNHEALTHY age: CHILD sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
18.5 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	1200 mg 2 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
22.06 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	1200 mg single, oral dose: 1200 mg route of administration: Oral experiment type: SINGLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: HIGH-FAT
28.05 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	1200 mg single, oral dose: 1200 mg route of administration: Oral experiment type: SINGLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED
15.46 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	20 mg/kg bw 2 times / day multiple, oral dose: 20 mg/kg bw route of administration: Oral experiment type: MULTIPLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: UNHEALTHY age: CHILD sex: UNKNOWN food status: UNKNOWN
8.73 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	15 mg/kg bw 3 times / day multiple, oral dose: 15 mg/kg bw route of administration: Oral experiment type: MULTIPLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: UNHEALTHY age: CHILD sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
8.85 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	1200 mg 2 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:		AMPRENAVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
10% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	1200 mg 2 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:		AMPRENAVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Co-administed with:: lamivudine, po(150 mg, BID) zidovudine, po(300 mg, BID) Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387	unhealthy, 21-62 n = 113 Health Status: unhealthy Condition: HIV-1 infection Age Group: 21-62 Sex: M+F Population Size: 113 Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387	Disc. AE: Nausea, Vomiting... AEs leading to discontinuation/dose reduction: Nausea (12%) Vomiting (6%) Loose stools (3%) Abdominal pain (2%) Abdominal discomfort (2%) Rash (3%) Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387
1200 mg single, oral Recommended Dose: 1200 mg Route: oral Route: single Dose: 1200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/10390223 Page: p.1688	unhealthy, 33+/-6.7 n = 12 Health Status: unhealthy Condition: HIV-1 infection Age Group: 33+/-6.7 Sex: M+F Population Size: 12 Sources: https://pubmed.ncbi.nlm.nih.gov/10390223 Page: p.1688	Sources: https://pubmed.ncbi.nlm.nih.gov/10390223 Page: p.1688
1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021007s017lbl.pdf Page: p.11	unhealthy Health Status: unhealthy Condition: HIV-1 infection Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021007s017lbl.pdf Page: p.11	Disc. AE: Reaction skin, Stevens-Johnson syndrome... AEs leading to discontinuation/dose reduction: Reaction skin (grade 3-4) Stevens-Johnson syndrome (grade 3-4) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021007s017lbl.pdf Page: p.11

AEs

AE	Significance	Dose	Population
Nausea	12% Disc. AE	1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Co-administed with:: lamivudine, po(150 mg, BID) zidovudine, po(300 mg, BID) Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387	unhealthy, 21-62 n = 113 Health Status: unhealthy Condition: HIV-1 infection Age Group: 21-62 Sex: M+F Population Size: 113 Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387
Abdominal discomfort	2% Disc. AE	1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Co-administed with:: lamivudine, po(150 mg, BID) zidovudine, po(300 mg, BID) Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387	unhealthy, 21-62 n = 113 Health Status: unhealthy Condition: HIV-1 infection Age Group: 21-62 Sex: M+F Population Size: 113 Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387
Abdominal pain	2% Disc. AE	1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Co-administed with:: lamivudine, po(150 mg, BID) zidovudine, po(300 mg, BID) Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387	unhealthy, 21-62 n = 113 Health Status: unhealthy Condition: HIV-1 infection Age Group: 21-62 Sex: M+F Population Size: 113 Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387
Loose stools	3% Disc. AE	1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Co-administed with:: lamivudine, po(150 mg, BID) zidovudine, po(300 mg, BID) Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387	unhealthy, 21-62 n = 113 Health Status: unhealthy Condition: HIV-1 infection Age Group: 21-62 Sex: M+F Population Size: 113 Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387
Rash	3% Disc. AE	1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Co-administed with:: lamivudine, po(150 mg, BID) zidovudine, po(300 mg, BID) Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387	unhealthy, 21-62 n = 113 Health Status: unhealthy Condition: HIV-1 infection Age Group: 21-62 Sex: M+F Population Size: 113 Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387
Vomiting	6% Disc. AE	1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Co-administed with:: lamivudine, po(150 mg, BID) zidovudine, po(300 mg, BID) Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387	unhealthy, 21-62 n = 113 Health Status: unhealthy Condition: HIV-1 infection Age Group: 21-62 Sex: M+F Population Size: 113 Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387
Reaction skin	grade 3-4 Disc. AE	1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021007s017lbl.pdf Page: p.11	unhealthy Health Status: unhealthy Condition: HIV-1 infection Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021007s017lbl.pdf Page: p.11
Stevens-Johnson syndrome	grade 3-4 Disc. AE	1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021007s017lbl.pdf Page: p.11	unhealthy Health Status: unhealthy Condition: HIV-1 infection Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021007s017lbl.pdf Page: p.11

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:40050	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:40050
ChemicalBook	CB4186139	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB4186139
MolPort	MolPort-000-883-856	https://www.molport.com/shop/molecule-link/MolPort-000-883-856
Selleck Chemicals	Amprenavir-(Agenerase)	http://www.selleckchem.com/products/Amprenavir-(Agenerase).html
ZINC	ZINC000003809192	http://zinc15.docking.org/substances/ZINC000003809192
eMolecules	877446	https://www.emolecules.com/cgi-bin/more?vid=877446

PubMed

Title	Date	PubMed
2',6'-Dimethylphenoxyacetyl: a new achiral high affinity P(3)-P(2) ligand for peptidomimetic-based HIV protease inhibitors.	2000 Mar 23	10737742
In vitro resistance profile of the human immunodeficiency virus type 1 protease inhibitor BMS-232632.	2000 Sep	10952574
Principles and practice of HIV-protease inhibitor pharmacoenhancement.	2001 Apr	11737387
Metabolic disposition and pharmacokinetics of [14C]-amprenavir, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, administered as a single oral dose to healthy male subjects.	2001 Apr	11304895
Open-label phase II trial of amprenavir, abacavir, and fixed-dose zidovudine/lamivudine in newly and chronically HIV-1--infected patients.	2001 Apr 1	11317074
Antiretrovirals: simultaneous determination of five protease inhibitors and three nonnucleoside transcriptase inhibitors in human plasma by a rapid high-performance liquid chromatography--mass spectrometry assay.	2001 Aug	11477320
Combination of protease inhibitors for the treatment of HIV-1-infected patients: a review of pharmacokinetics and clinical experience.	2001 Dec	11878403
Therapeutic drug monitoring of HIV protease inhibitors using high-performance liquid chromatography with ultraviolet or photodiode array detection.	2001 Dec	11802104
Human immunodeficiency virus type 1 hypersusceptibility to amprenavir in vitro can be associated with virus load response to treatment in vivo.	2001 Dec 15	11700580
Safety profile and tolerability of amprenavir in patients enrolled in an early access program.	2001 Feb	11293558
New developments in anti-HIV chemotherapy.	2001 Jan-Feb	11347962
Possible linkage of amprenavir with intracranial bleeding in an HIV-infected hemophiliac.	2001 Jul	11483161
Capillary electrophoretic separation of protease inhibitors used in human immunodeficiency virus therapy.	2001 Jul 13	11486877
High-performance liquid chromatographic assay to determine the plasma levels of HIV-protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir and saquinavir) and the non-nucleoside reverse transcriptase inhibitor (nevirapine) after liquid-liquid extraction.	2001 Jul 15	11486821
Synthesis of a chiral aziridine derivative as a versatile intermediate for HIV protease inhibitors.	2001 Jul 26	11463313
Amprenavir: new preparation. Another HIV protease inhibitor: no proven advance.	2001 Jun	11718166
Effect of reduced-dose amprenavir in combination with lopinavir on plasma levels of amprenavir in patients infected with HIV.	2001 Mar	11318084
[Simultaneous quantitative determination of amprenavir and indinavir in human plasma by high-performance liquid chromatography].	2001 Mar-Apr	11282520
Resistant to everything.	2001 May	11682786
Induction of P-glycoprotein and cytochrome P450 3A by HIV protease inhibitors.	2001 May	11302944
[Drug interactions with antiretroviral agents].	2001 May-Jun	11475806
Anti-human immunodeficiency virus drugs are ineffective against Pneumocystis carinii in vitro and in vivo.	2001 Nov 15	11679930
Pharmacokinetics of amprenavir and lopinavir in combination with nevirapine in highly pretreated HIV-infected patients.	2001 Nov 23	11698713
In vitro activity of amprenavir against Pneumocystis carinii.	2001 Sep	11708264
Mismatched double-stranded RNA (polyI-polyC(12)U) is synergistic with multiple anti-HIV drugs and is active against drug-sensitive and drug-resistant HIV-1 in vitro.	2001 Sep	11448730
Amping amprenavir with ritonavir.	2001 Spring	11570075
Clinical pharmacology and pharmacokinetics of amprenavir.	2002 Jan	11816239
Determination of amprenavir, a HIV-1 protease inhibitor, in human seminal plasma using high-performance liquid chromatography-tandem mass spectrometry.	2002 Jan 25	11824819
New developments in anti-HIV chemotherapy.	2002 Jul 18	12084468
Sensitive and simultaneous determination of HIV protease inhibitors in rat biological samples by liquid chromatography-mass spectrometry.	2002 Jun	11933027
Fosamprenavir. Vertex Pharmaceuticals/GlaxoSmithKline.	2002 Mar	12054084
Lipodystrophy update.	2002 Mar	12038302
Drug interactions between HIV protease inhibitors based on physiologically-based pharmacokinetic model.	2002 Mar	11920753
Efavirenz-induced skin eruption and successful desensitization.	2002 Mar	11895054
The utility of inhibitory quotients in determining the relative potency of protease inhibitors.	2002 Mar 29	11964541
Drug interaction between amprenavir and lopinavir/ritonavir in salvage therapy.	2002 Mar 29	11964539
FDA approves new dosing for amprenavir and ritonavir combination.	2002 Mar 8	11965920
Prevalence of the HIV protease mutation N88S causing hypersensitivity to amprenavir.	2002 May 1	11941567
Amprenavir-resistant HIV-1 exhibits lopinavir cross-resistance and reduced replication capacity.	2002 May 3	11953467
Select HIV protease inhibitors alter bone and fat metabolism ex vivo.	2002 May 31	11937496

Patents

Sample Use Guides

In Vivo Use Guide

Adults: The recommended oral dose of AGENERASE Capsules for adults is 1200 mg (eight 150-mg capsules) twice daily in combination with other antiretroviral agents. Concomitant Therapy: If AGENERASE and ritonavir are used in combination, the recommended dosage regimens are: AGENERASE 1200 mg with ritonavir 200 mg once daily or AGENERASE 600 mg with ritonavir 100 mg twice daily. Pediatric Patients: For adolescents (13 to 16 years), the recommended oral dose of AGENERASE Capsules is 1200 mg (eight 150-mg capsules) twice daily in combination with other antiretroviral agents. For patients between 4 and 12 years of age or for patients 13 to 16 years of age with weight of <50 kg, the recommended oral dose of AGENERASE Capsules is 20 mg/kg twice daily or 15 mg/kg 3 times daily (to a maximum daily dose of 2400 mg) in combination with other antiretroviral agents.

Route of Administration: Oral

In Vitro Use Guide

The in vitro antiviral activity of amprenavir was evaluated against HIV-1 IIIB in both acutely and chronically infected lymphoblastic cell lines (MT-4, CEM-CCRF, 43 H9) and in peripheral blood lymphocytes. The 50% inhibitory concentration (IC50) of amprenavir ranged from 0.012 to 0.08 µM in acutely infected cells and was 0.41 µM in chronically infected cells (1 µM = 0.50 mcg/mL).

Substance Class	Chemical Created by `admin` on `Fri Dec 16 18:15:59 UTC 2022` Edited by `admin` on `Fri Dec 16 18:15:59 UTC 2022`
Record UNII	5S0W860XNR
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

AMPRENAVIR

Official Name

English

AMPRENAVIR [EMA EPAR]

Common Name

English

VX-478

Code

English

AMPRENAVIR [VANDF]

Common Name

English

AMPRENAVIR [MART.]

Common Name

English

KVX-478

Code

English

(3S-(3R*(1R*,2S*)))-(3-(((4-AMINOPHENYL)SULFONYL)(2-METHYLPROPYL)AMINO)-2-HYDROXY-1-(PHENYLMETHYL)PROPYL) TETRAHYDRO-3-FURANYL CARBAMATE

Common Name

English

AMPRENAVIR [MI]

Common Name

English

AMPRENAVIR [HSDB]

Common Name

English

141 W94

Code

English

AMPRENAVIR [ORANGE BOOK]

Common Name

English

J05AE05

Code

English

AMPRENAVIR [USAN]

Common Name

English

AGENERASE

Brand Name

English

AMPRENAVIR [JAN]

Common Name

English

Amprenavir [WHO-DD]

Common Name

English

amprenavir [INN]

Common Name

English

141W94

Code

English

(3S)-Tetrahydro-3-furyl [(?S)-?-[(1R-1-hydroxy-2-(N1-isobutylsulfanilamido)ethyl]phenethyl]carbamate

Common Name

English

Classification Tree Code System Code

EMA ASSESSMENT REPORTS

AGENERASE (WITHDRAWN: HIV INFECTIONS)