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
- 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.
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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.
Target Actions Organism UHuman immunodeficiency virus type 1 protease Not Available Human 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
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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 show 12 more
- Substituents
- 2,4-disubstituted 1,3-thiazole / Acetal / Alcohol / Alkyl aryl ether / Aminosulfonyl compound / Amphetamine or derivatives / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzodioxole show 26 more
- 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
- 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]
- 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]
- 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]
- 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]
- External Links
- 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
Phase Status Purpose Conditions Count 2 Completed Treatment Human Immunodeficiency Virus (HIV) Infections / Human Immunodeficiency Virus Type 1 (HIV-1) Infection 1 2 Terminated Treatment Human Immunodeficiency Virus Type 1 (HIV-1) Infection 1
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
Property Value Source Water Solubility 0.0177 mg/mL ALOGPS logP 2.99 ALOGPS logP 3.7 Chemaxon logS -4.6 ALOGPS pKa (Strongest Acidic) 13.18 Chemaxon pKa (Strongest Basic) 2.6 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 10 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 154.98 Å2 Chemaxon Rotatable Bond Count 14 Chemaxon Refractivity 173.61 m3·mol-1 Chemaxon Polarizability 73.53 Å3 Chemaxon Number of Rings 6 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.8503 Blood Brain Barrier - 0.6259 Caco-2 permeable - 0.5498 P-glycoprotein substrate Substrate 0.7827 P-glycoprotein inhibitor I Inhibitor 0.6105 P-glycoprotein inhibitor II Non-inhibitor 0.8123 Renal organic cation transporter Non-inhibitor 0.8635 CYP450 2C9 substrate Non-substrate 0.6533 CYP450 2D6 substrate Non-substrate 0.6656 CYP450 3A4 substrate Substrate 0.6509 CYP450 1A2 substrate Non-inhibitor 0.684 CYP450 2C9 inhibitor Non-inhibitor 0.63 CYP450 2D6 inhibitor Non-inhibitor 0.8452 CYP450 2C19 inhibitor Non-inhibitor 0.6432 CYP450 3A4 inhibitor Inhibitor 0.8292 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.6233 Ames test Non AMES toxic 0.5913 Carcinogenicity Non-carcinogens 0.7351 Biodegradation Not ready biodegradable 1.0 Rat acute toxicity 2.6131 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9801 hERG inhibition (predictor II) Non-inhibitor 0.6799
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 272.2840621 predictedDarkChem Lite v0.1.0 [M-H]- 254.72008 predictedDeepCCS 1.0 (2019) [M+H]+ 270.4345621 predictedDarkChem Lite v0.1.0 [M+H]+ 257.11566 predictedDeepCCS 1.0 (2019) [M+Na]+ 273.6473621 predictedDarkChem Lite v0.1.0 [M+Na]+ 263.3119 predictedDeepCCS 1.0 (2019)
Targets
- 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
- 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]
- 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]
- 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 at October 21, 2007 13:33 / Updated at February 21, 2021 18:51