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Identification
Name Darunavir
Accession Number DB01264 (EXPT00002)
Type small molecule
Groups approved
Description

Darunavir is a protease inhibitor used to treat HIV. It acts on the HIV aspartyl protease which the virus needs to cleave the HIV polyprotein into its functional fragments.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • AIDS073035
  • Darunavirum [INN-latin]
  • TMC-114
  • TMC114
  • UIC-94017
Brand names
  • Prezista (Tibotec Therapeutics)
Brand name mixtures Not Available
Categories
  • Antiviral Agents
  • HIV Protease Inhibitors
CAS number 206361-99-1
Weight Average: 547.664
Monoisotopic: 547.235221243
Chemical Formula C27H37N3O7S
InChI Key InChIKey=CJBJHOAVZSMMDJ-HEXNFIEUSA-N
InChI
InChI=1S/C27H37N3O7S/c1-18(2)15-30(38(33,34)21-10-8-20(28)9-11-21)16-24(31)23(14-19-6-4-3-5-7-19)29-27(32)37-25-17-36-26-22(25)12-13-35-26/h3-11,18,22-26,31H,12-17,28H2,1-2H3,(H,29,32)/t22-,23-,24+,25-,26+/m0/s1
Plain Text
IUPAC Name
(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl N-[(2S,3R)-3-hydroxy-4-[N-(2-methylpropyl)(4-aminobenzene)sulfonamido]-1-phenylbutan-2-yl]carbamate
SMILES
[H][C@]12OCC[C@@]1([H])[C@H](CO2)OC(=O)N[C@@H](CC1=CC=CC=C1)[C@H](O)CN(CC(C)C)S(=O)(=O)C1=CC=C(N)C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Benzenesulfonamides
  • Sulfanilamides
  • Amphetamines
Substructures
  • Hydroxy Compounds
  • Acetals and Derivatives
  • Carbamates and Derivatives
  • Sulfonyls
  • Aliphatic and Aryl Amines
  • Ethers
  • Benzene and Derivatives
  • Benzenesulfonamides
  • Phenethylamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Sulfanilamides
  • Sulfonamides
  • Furans
  • Alcohols and Polyols
  • Anilines
  • Amphetamines
Pharmacology
Indication Darunavir, co-administered with ritonavir, and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV) infection in antiretroviral treatment-experienced adult patients, such as those with HIV-1 strains resistant to more than one protease inhibitor.
Pharmacodynamics Darunavir is an inhibitor of the human immunodeficiency virus (HIV) protease. In studies, the drug, co-administered with ritonavir in combination therapy, significantly reduced viral load and increased CD4 cell counts in this treatment-experienced patient population (Tibotec, 2006, Product Monograph, Prezista 2006). Darunavir is used as an adjunct therapy with low dose ritonavir, which inhibits cytochrome P450 3A (CYP3A) which increases the bioavailability and half life of darunavir.
Mechanism of action Darunavir is a HIV protease inhibitor which prevents HIV replication by binding to the enzyme's active site, thereby preventing the dimerization and the catalytic activity of the HIV-1 protease. Darunavir selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus-infected cells, which prevents the formation of mature infectious virus particles. Structual analyses suggests that the close contact that darunavir has with the main chains of the protease active site amino acids (Asp-29 and Asp-30) is an important contributing factor to its potency and wide spectrum of activity against multi-protease inhibitor resistant HIV-1 variants. Darunavir can also adapt to the changing shape of a protease enzyme because of its molecular flexibility. Darunavir is known to bind to two distinct sites on the enzyme: the active site cavity and the surface of one of the flexible flaps in the protease dimer.
Absorption The absolute oral bioavailability of a single 600 mg dose of darunavir alone and after co-administration with 100 mg ritonavir twice daily was 37% and 82%, respectively.
Volume of distribution Not Available
Protein binding Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).
Metabolism

Hepatic. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A.
Route of elimination Darunavir is primarily metabolized by CYP3A. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A. A mass balance study in healthy volunteers showed that after single dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir was recovered in the feces and urine, respectively.
Half life The terminal elimination half-life of darunavir was approximately 15 hours when combined with ritonavir.
Clearance
  • 32.8 L/hr [Healthy volunteers receiving intravenous administration of 400 mg of darunavir]
  • 5.9 L/hr [Healthy volunteers receiving intravenous administrations of 400 mg of darunavir and 100 mg of ritonavir twice daily]
Toxicity Not Available
Affected organisms
  • Human Immunodeficiency Virus
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Tibotec inc
  • Centocor Ortho Biotech, Inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Prezista 600 mg tablet 25.75 USD tablet
Prezista 400 mg tablet 18.74 USD tablet
Prezista 300 mg tablet 16.2 USD tablet
Prezista 150 mg tablet 4.59 USD tablet
Prezista 75 mg tablet 2.3 USD tablet
Patents
Country Patent Number Approved Expires
United States 7700645 2006-12-26 2026-12-26
United States 6335460 1992-08-25 2012-08-25
Canada 2469343 2008-05-13 2022-12-12
Canada 2224738 2002-08-27 2016-06-28
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility Approximately 0.15 mg/mL at 20°C as ethanolate salt PhysProp
logP 1.8 PhysProp
Predicted Properties
Property Value Source
water solubility 6.68e-02 g/l ALOGPS
logP 1.76 ALOGPS
logP 2.82 ChemAxon Molconvert
logS -3.91 ALOGPS
pKa 14.23 ChemAxon Molconvert
hydrogen acceptor count 7 ChemAxon Molconvert
hydrogen donor count 3 ChemAxon Molconvert
polar surface area 140.42 ChemAxon Molconvert
rotatable bond count 11 ChemAxon Molconvert
refractivity 142.34 ChemAxon Molconvert
polarizability 57.24 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Back D, Sekar V, Hoetelmans RM: Darunavir: pharmacokinetics and drug interactions. Antivir Ther. 2008;13(1):1-13. Pubmed
  2. Medilexicon Link
  3. Company Website Link
  4. Tremblay CL: Combating HIV resistance – focus on darunavir. Ther Clin Risk Manag. 2008 Aug;4(4):759-66. Pubmed
  5. Koh Y, Matsumi S, Das D, Amano M, Davis DA, Li J, Leschenko S, Baldridge A, Shioda T, Yarchoan R, Ghosh AK, Mitsuya H: Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization. J Biol Chem. 2007 Sep 28;282(39):28709-20. Epub 2007 Jul 17. Pubmed
  6. Kovalevsky AY, Tie Y, Liu F, Boross PI, Wang YF, Leshchenko S, Ghosh AK, Harrison RW, Weber IT: Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M. J Med Chem. 2006 Feb 23;49(4):1379-87. Pubmed
  7. De Meyer S, Azijn H, Surleraux D, Jochmans D, Tahri A, Pauwels R, Wigerinck P, de Bethune MP: TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. Antimicrob Agents Chemother. 2005 Jun;49(6):2314-21. Pubmed
External Links
Resource Link
KEGG Drug D03656 Link_out
PubChem Compound 213039 Link_out
PubChem Substance 46506908 Link_out
ChemSpider 184733 Link_out
BindingDB 8125 Link_out
ChEBI 367163 Link_out
ChEMBL 367163 Link_out
Therapeutic Targets Database DAP001086 Link_out
Drug Product Database 2284057 Link_out
RxList http://www.rxlist.com/cgi/generic/prezista.htm Link_out
Drugs.com http://www.drugs.com/cdi/darunavir.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Darunavir Link_out
ATC Codes
  • J05AE10
AHFS Codes
  • 08:18.08.08
PDB Entries Not Available
FDA label show (281.1 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions
  • Take with food - better absorption (+30%).
Targets

1. HIV-1 protease

Pharmacological action: yes
Actions: inhibitor
Organism class: viral
UniProt ID: O90777 Link_out
Gene: HIV-1 protease
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Dierynck I, De Wit M, Gustin E, Keuleers I, Vandersmissen J, Hallenberger S, Hertogs K: Binding kinetics of darunavir to HIV-1 protease explain the potent antiviral activity and high genetic barrier. J Virol. 2007 Oct 10;. Pubmed
  4. Ghosh AK, Dawson ZL, Mitsuya H: Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV. Bioorg Med Chem. 2007 Sep 14;. Pubmed
  5. Wang YF, Tie Y, Boross PI, Tozser J, Ghosh AK, Harrison RW, Weber IT: Potent new antiviral compound shows similar inhibition and structural interactions with drug resistant mutants and wild type HIV-1 protease. J Med Chem. 2007 Sep 6;50(18):4509-15. Epub 2007 Aug 16. Pubmed
  6. McKeage K, Perry CM, Keam SJ: Darunavir: a review of its use in the management of HIV infection in adults. Drugs. 2009;69(4):477-503. Pubmed
  7. Tremblay CL: Combating HIV resistance – focus on darunavir. Ther Clin Risk Manag. 2008 Aug;4(4):759-66. Pubmed
  8. Kovalevsky AY, Tie Y, Liu F, Boross PI, Wang YF, Leshchenko S, Ghosh AK, Harrison RW, Weber IT: Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M. J Med Chem. 2006 Feb 23;49(4):1379-87. Pubmed
  9. De Meyer S, Azijn H, Surleraux D, Jochmans D, Tahri A, Pauwels R, Wigerinck P, de Bethune MP: TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. Antimicrob Agents Chemother. 2005 Jun;49(6):2314-21. Pubmed
  10. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. McKeage K, Perry CM, Keam SJ: Darunavir: a review of its use in the management of HIV infection in adults. Drugs. 2009;69(4):477-503. Pubmed
  2. Tremblay CL: Combating HIV resistance – focus on darunavir. Ther Clin Risk Manag. 2008 Aug;4(4):759-66. Pubmed
Comments
Drug created on May 16, 2007 11:43 / Updated on April 19, 2011 15:09

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.