Brecanavir

Identification

Generic Name
Brecanavir
DrugBank Accession Number
DB04887
Background

Brecanavir (VX-385) an orally active aspartic protease inhibitor (PI), under investigation by Vertex and GlaxoSmithKline for the treatment of HIV. In July 2006, Vertex indicated that it expected GSK to initiate phase III trials of the drug in 2007. In December of 2006 GSK announced a decision to discontinue the development of brecanavir for the treatment of HIV. The decision was based on issues regarding the formulation of the drug.

Type
Small Molecule
Groups
Investigational
Structure
Thumb
Weight
Average: 703.823
Monoisotopic: 703.223335927
Chemical Formula
C33H41N3O10S2
Synonyms
  • Brecanavir
External IDs
  • GSK 640385
  • GW 0385
  • GW-640385
  • GW-640385X
  • GW-64085X
  • GW640385
  • GW64085X
  • VX 385
  • VX-385

Pharmacology

Indication

For the treatment of HIV-1 infection in combination with other antiretroviral agents.

Pharmacology
Reduce drug development failure rates
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Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Brecanavir is an orally active aspartic protease inhibitor (PI) under investigation by Vertex and GlaxoSmithKline for the treatment of HIV. Test-tube data suggest that it has activity against virus with resistance to the currently available protease inhibitors, and that it is more powerful against wild-type HIV that existing protease inhibitors, being active at concentrations much lower than most existing protease inhibitors. Unlike some other protease inhibitors, brecanavir does not have a significant interaction with the nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir (Viread). In December of 2006 GlaxoSmithKline announced their decision to discontinue the development of brecanavir for the treatment of HIV. The decision was based on issues regarding the formulation of the drug.

Mechanism of action

Brecanavir inhibits the HIV viral proteinase enzyme which prevents cleavage of the gag-pol polyprotein, resulting in noninfectious, immature viral particles.

TargetActionsOrganism
UHuman immunodeficiency virus type 1 proteaseNot AvailableHuman immunodeficiency virus 1
Absorption

Brecanavir, a CYP3A4 substrate, demonstrated low oral bioavailability in animals (0 to 30%), which increased to 60 to 100% following coadministration with oral ritonavir (a potent CYP3A inhibitor).

Volume of distribution

Not Available

Protein binding

Estimated be 97 to 98%

Metabolism

Brecanavir is a known substrate of CYP450 3A4, the most important cytochrome P450 isoenzyme involved in metabolizing PIs and non-nucleoside reverse transcriptase inhibitors.

Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenylbutylamines. These are compounds containing a phenylbutylamine moiety, which consists of a phenyl group substituted at the fourth carbon by an butan-1-amine.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Phenylbutylamines
Direct Parent
Phenylbutylamines
Alternative Parents
Amphetamines and derivatives / Benzodioxoles / Phenoxy compounds / Phenol ethers / Furofurans / 2,4-disubstituted thiazoles / Alkyl aryl ethers / Organosulfonamides / Tetrahydrofurans / Aminosulfonyl compounds
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Substituents
2,4-disubstituted 1,3-thiazole / Acetal / Alcohol / Alkyl aryl ether / Aminosulfonyl compound / Amphetamine or derivatives / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzodioxole
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Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Human Immunodeficiency Virus

Chemical Identifiers

UNII
E367I8C7FI
CAS number
313682-08-5
InChI Key
JORVRJNILJXMMG-OLNQLETPSA-N
InChI
InChI=1S/C33H41N3O10S2/c1-20(2)14-36(48(39,40)25-8-9-29-30(13-25)45-19-44-29)15-28(37)27(35-33(38)46-31-17-43-32-26(31)10-11-41-32)12-22-4-6-24(7-5-22)42-16-23-18-47-21(3)34-23/h4-9,13,18,20,26-28,31-32,37H,10-12,14-17,19H2,1-3H3,(H,35,38)/t26-,27-,28+,31-,32+/m0/s1
IUPAC Name
(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl N-[(2S,3R)-3-hydroxy-1-{4-[(2-methyl-1,3-thiazol-4-yl)methoxy]phenyl}-4-[N-(2-methylpropyl)2H-1,3-benzodioxole-5-sulfonamido]butan-2-yl]carbamate
SMILES
[H][C@]12OCC[C@@]1([H])[C@H](CO2)OC(=O)N[C@@H](CC1=CC=C(OCC2=CSC(C)=N2)C=C1)[C@H](O)CN(CC(C)C)S(=O)(=O)C1=CC2=C(OCO2)C=C1

References

General References
  1. Hazen R, Harvey R, Ferris R, Craig C, Yates P, Griffin P, Miller J, Kaldor I, Ray J, Samano V, Furfine E, Spaltenstein A, Hale M, Tung R, St Clair M, Hanlon M, Boone L: In vitro antiviral activity of the novel, tyrosyl-based human immunodeficiency virus (HIV) type 1 protease inhibitor brecanavir (GW640385) in combination with other antiretrovirals and against a panel of protease inhibitor-resistant HIV. Antimicrob Agents Chemother. 2007 Sep;51(9):3147-54. Epub 2007 Jul 9. [Article]
  2. Lalezari JP, Ward DJ, Tomkins SA, Garges HP: Preliminary safety and efficacy data of brecanavir, a novel HIV-1 protease inhibitor: 24 week data from study HPR10006. J Antimicrob Chemother. 2007 Jul;60(1):170-4. Epub 2007 May 8. [Article]
  3. Reddy YS, Ford SL, Anderson MT, Murray SC, Ng-Cashin J, Johnson MA: Safety and pharmacokinetics of brecanavir, a novel human immunodeficiency virus type 1 protease inhibitor, following repeat administration with and without ritonavir in healthy adult subjects. Antimicrob Agents Chemother. 2007 Apr;51(4):1202-8. Epub 2007 Jan 29. [Article]
  4. Ford SL, Reddy YS, Anderson MT, Murray SC, Fernandez P, Stein DS, Johnson MA: Single-dose safety and pharmacokinetics of brecanavir, a novel human immunodeficiency virus protease inhibitor. Antimicrob Agents Chemother. 2006 Jun;50(6):2201-6. [Article]
KEGG Drug
D03253
PubChem Compound
5743186
PubChem Substance
175426890
ChemSpider
4675192
BindingDB
4685
ChEMBL
CHEMBL206031
ZINC
ZINC000003994828
PDBe Ligand
385
Wikipedia
Brecanavir
PDB Entries
2fdd / 2fde

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Human Immunodeficiency Virus Type 1 (HIV-1) Infection1
2TerminatedTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1) Infection1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0177 mg/mLALOGPS
logP2.99ALOGPS
logP3.7ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)13.18ChemAxon
pKa (Strongest Basic)2.6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area154.98 Å2ChemAxon
Rotatable Bond Count14ChemAxon
Refractivity173.61 m3·mol-1ChemAxon
Polarizability73.3 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.8503
Blood Brain Barrier-0.6259
Caco-2 permeable-0.5498
P-glycoprotein substrateSubstrate0.7827
P-glycoprotein inhibitor IInhibitor0.6105
P-glycoprotein inhibitor IINon-inhibitor0.8123
Renal organic cation transporterNon-inhibitor0.8635
CYP450 2C9 substrateNon-substrate0.6533
CYP450 2D6 substrateNon-substrate0.6656
CYP450 3A4 substrateSubstrate0.6509
CYP450 1A2 substrateNon-inhibitor0.684
CYP450 2C9 inhibitorNon-inhibitor0.63
CYP450 2D6 inhibitorNon-inhibitor0.8452
CYP450 2C19 inhibitorNon-inhibitor0.6432
CYP450 3A4 inhibitorInhibitor0.8292
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6233
Ames testNon AMES toxic0.5913
CarcinogenicityNon-carcinogens0.7351
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6131 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9801
hERG inhibition (predictor II)Non-inhibitor0.6799
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets2
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Kind
Protein
Organism
Human immunodeficiency virus 1
Pharmacological action
Unknown
General Function
Aspartic-type endopeptidase activity
Specific Function
Not Available
Gene Name
pol
Uniprot ID
Q72874
Uniprot Name
Pol polyprotein
Molecular Weight
10778.7 Da
References
  1. Hazen R, Harvey R, Ferris R, Craig C, Yates P, Griffin P, Miller J, Kaldor I, Ray J, Samano V, Furfine E, Spaltenstein A, Hale M, Tung R, St Clair M, Hanlon M, Boone L: In vitro antiviral activity of the novel, tyrosyl-based human immunodeficiency virus (HIV) type 1 protease inhibitor brecanavir (GW640385) in combination with other antiretrovirals and against a panel of protease inhibitor-resistant HIV. Antimicrob Agents Chemother. 2007 Sep;51(9):3147-54. Epub 2007 Jul 9. [Article]
  2. Ford SL, Reddy YS, Anderson MT, Murray SC, Fernandez P, Stein DS, Johnson MA: Single-dose safety and pharmacokinetics of brecanavir, a novel human immunodeficiency virus protease inhibitor. Antimicrob Agents Chemother. 2006 Jun;50(6):2201-6. [Article]
  3. Reddy YS, Ford SL, Anderson MT, Murray SC, Ng-Cashin J, Johnson MA: Safety and pharmacokinetics of brecanavir, a novel human immunodeficiency virus type 1 protease inhibitor, following repeat administration with and without ritonavir in healthy adult subjects. Antimicrob Agents Chemother. 2007 Apr;51(4):1202-8. Epub 2007 Jan 29. [Article]

Drug created on October 21, 2007 13:33 / Updated on February 21, 2021 18:51