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targets (1) enzymes (3)
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Identification
Name Tipranavir
Accession Number DB00932 (APRD01306)
Type small molecule
Groups approved
Description

Tipranavir is a sulfonamide-containing dyhydropyrone and a nonpeptidic protease inhibitor that targets the HIV protease. It is administered with ritonavir in combination therapy to treat HIV infections.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • tipranavir
  • TPV
Brand names
  • Aptivus
  • Aptivus (Boehringer Ingelheim)
Brand name mixtures Not Available
Categories
  • Anti-HIV Agents
  • HIV Protease Inhibitors
CAS number 174484-41-4
Weight Average: 602.664
Monoisotopic: 602.206227481
Chemical Formula C31H33F3N2O5S
InChI Key InChIKey=NZPXPXAGXYTROM-FYBSXPHGSA-N
InChI
InChI=1S/C31H33F3N2O5S/c1-3-16-30(17-15-21-9-6-5-7-10-21)19-26(37)28(29(38)41-30)25(4-2)22-11-8-12-24(18-22)36-42(39,40)27-14-13-23(20-35-27)31(32,33)34/h5-14,18,20,25,36,38H,3-4,15-17,19H2,1-2H3/t25-,30-/m1/s1
Plain Text
IUPAC Name
N-{3-[(1R)-1-[(2R)-6-hydroxy-4-oxo-2-(2-phenylethyl)-2-propyl-3,4-dihydro-2H-pyran-5-yl]propyl]phenyl}-5-(trifluoromethyl)pyridine-2-sulfonamide
SMILES
CCC[C@@]1(CCC2=CC=CC=C2)CC(=O)C([C@H](CC)C2=CC(NS(=O)(=O)C3=NC=C(C=C3)C(F)(F)F)=CC=C2)=C(O)O1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Pyrans
  • Pyridines and Derivatives
  • Benzene and Derivatives
  • Carboxylic Acids and Derivatives
  • Anilines
Substructures
  • Hydroxy Compounds
  • Pyrans
  • Pyridines and Derivatives
  • Sulfonyls
  • Ethers
  • Halogen Derivatives
  • Benzene and Derivatives
  • Carboxylic Acids and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Ketenes and Derivatives
  • Sulfonamides
  • Anilines
  • Ketones
Pharmacology
Indication For combination antiretroviral treatment of HIV-1 infected adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors.
Pharmacodynamics Tipranavir is a non-peptidic protease inhibitor (PI) of HIV. Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Nelfinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs.
Mechanism of action Tipranavir (TPV) is a non-peptidic HIV-1 protease inhibitor that inhibits the processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. Two mechanisms are suggested in regards to the potency of tipranavir: 1. Tipravanir may bind to the active site of the protease enzyme with fewer hydrogen bonds than peptidic protease inhibitors, which results in increased flexibility, allowing it to fit into the active site of the enzyme in viruses that have become resistance to other protease inhibitors. This also enables tipranavir to adjust to amino acid substitutions at the active site. 2. Tipranavir's strong hydrogen bonding interaction with the amide backbone of the protease active site Asp30 may lead to its activity against resistant viruses.
Absorption Absorption is limited, although no absolute quantification of absorption is available.
Volume of distribution Not Available
Protein binding Extensive (> 99.9%), to both human serum albumin and α-1-acid glycoprotein.
Metabolism

Hepatic. In vitro metabolism studies with human liver microsomes indicated that CYP 3A4 is the predominant CYP enzyme involved in tipranavir metabolism.
Route of elimination Not Available
Half life 5-6 hours
Clearance Not Available
Toxicity Oral LD50 in rat is over 5,000 mg/kg. Side effects include thirst and hunger, unexplained weight loss, increased urination, fatigue, and dry, itchy skin.
Affected organisms
  • Human Immunodeficiency Virus
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Boehringer ingelheim pharmaceuticals inc
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Prices
Unit description Cost Unit
Aptivus 120 250 mg capsule Bottle 1271.8 USD bottle
Aptivus 250 mg capsule 10.19 USD capsule
Aptivus 100 mg/ml solution 4.29 USD ml
Patents
Country Patent Number Approved Expires
United States 6147095 2000-04-29 2020-04-29
United States 6169181 1994-05-06 2014-05-06
Canada 2294033 2007-01-09 2018-07-27
Canada 2187523 2006-11-21 2015-05-04
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility Insoluble PhysProp
logP 6.9 PhysProp
Predicted Properties
Property Value Source
water solubility 2.07e-04 g/l ALOGPS
logP 5.71 ALOGPS
logP 7.81 ChemAxon Molconvert
logS -6.46 ALOGPS
pKa 7.84 ChemAxon Molconvert
hydrogen acceptor count 6 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 105.59 ChemAxon Molconvert
rotatable bond count 11 ChemAxon Molconvert
refractivity 163.56 ChemAxon Molconvert
polarizability 61.31 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Doyon L, Tremblay S, Bourgon L, Wardrop E, Cordingley MG: Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir. Antiviral Res. 2005 Oct;68(1):27-35. Pubmed
  2. Tipranavir: PNU 140690, tipranivir. Drugs R D. 2006;7(1):55-62. Pubmed
  3. Temesgen Z, Feinberg J: Tipranavir: a new option for the treatment of drug-resistant HIV infection. Clin Infect Dis. 2007 Sep 15;45(6):761-9. Epub 2007 Aug 7. Pubmed
  4. Luna B, Townsend MU: Tipranavir: the first nonpeptidic protease inhibitor for the treatment of protease resistance. Clin Ther. 2007 Nov;29(11):2309-18. Pubmed
External Links
Resource Link
PubChem Compound 65027 Link_out
PubChem Substance 46506257 Link_out
ChemSpider 58539 Link_out
BindingDB 558 Link_out
Therapeutic Targets Database DAP001085 Link_out
HET TPV Link_out
Drug Product Database 2273322 Link_out
RxList http://www.rxlist.com/cgi/generic/aptivus.htm Link_out
Drugs.com http://www.drugs.com/cdi/tipranavir.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Tipranavir Link_out
ATC Codes
  • J05AE09
AHFS Codes
  • 08:18.08.08
PDB Entries Not Available
FDA label show (387.7 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
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. 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
  5. Tenore SB, Ferreira PR: The Place of protease inhibitors in antiretroviral treatment. Braz J Infect Dis. 2009 Oct;13(5):371-4. Pubmed
  6. Muzammil S, Armstrong AA, Kang LW, Jakalian A, Bonneau PR, Schmelmer V, Amzel LM, Freire E: Unique thermodynamic response of tipranavir to human immunodeficiency virus type 1 protease drug resistance mutations. J Virol. 2007 May;81(10):5144-54. Epub 2007 Mar 14. Pubmed
  7. Hsieh SM, Chang SY, Hung CC, Sheng WH, Chen MY, Chang SC: Impact of first-line protease inhibitors on predicted resistance to tipranavir in HIV-1-infected patients with virological failure. BMC Infect Dis. 2009 Sep 14;9:154. Pubmed
  8. Temesgen Z, Feinberg J: Tipranavir: a new option for the treatment of drug-resistant HIV infection. Clin Infect Dis. 2007 Sep 15;45(6):761-9. Epub 2007 Aug 7. Pubmed
  9. Luna B, Townsend MU: Tipranavir: the first nonpeptidic protease inhibitor for the treatment of protease resistance. Clin Ther. 2007 Nov;29(11):2309-18. Pubmed
  10. Croom KF, Keam SJ: Tipranavir: a ritonavir-boosted protease inhibitor. Drugs. 2005;65(12):1669-77; discussion 1678-9. Pubmed
  11. 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. Temesgen Z, Feinberg J: Tipranavir: a new option for the treatment of drug-resistant HIV infection. Clin Infect Dis. 2007 Sep 15;45(6):761-9. Epub 2007 Aug 7. Pubmed
  2. Luna B, Townsend MU: Tipranavir: the first nonpeptidic protease inhibitor for the treatment of protease resistance. Clin Ther. 2007 Nov;29(11):2309-18. Pubmed
  3. Li F, Wang L, Guo GL, Ma X: Metabolism-mediated drug interactions associated with ritonavir-boosted tipranavir in mice. Drug Metab Dispos. 2010 May;38(5):871-8. Epub 2010 Jan 26. Pubmed
  4. Dumond JB, Vourvahis M, Rezk NL, Patterson KB, Tien HC, White N, Jennings SH, Choi SO, Li J, Wagner MJ, La-Beck NM, Drulak M, Sabo JP, Castles MA, Macgregor TR, Kashuba AD: A phenotype-genotype approach to predicting CYP450 and P-glycoprotein drug interactions with the mixed inhibitor/inducer tipranavir/ritonavir. Clin Pharmacol Ther. 2010 Jun;87(6):735-42. Epub 2010 Feb 10. Pubmed

2. Cytochrome P450 2D6

Actions: substrate, inhibitor

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Li F, Wang L, Guo GL, Ma X: Metabolism-mediated drug interactions associated with ritonavir-boosted tipranavir in mice. Drug Metab Dispos. 2010 May;38(5):871-8. Epub 2010 Jan 26. Pubmed
  2. Dumond JB, Vourvahis M, Rezk NL, Patterson KB, Tien HC, White N, Jennings SH, Choi SO, Li J, Wagner MJ, La-Beck NM, Drulak M, Sabo JP, Castles MA, Macgregor TR, Kashuba AD: A phenotype-genotype approach to predicting CYP450 and P-glycoprotein drug interactions with the mixed inhibitor/inducer tipranavir/ritonavir. Clin Pharmacol Ther. 2010 Jun;87(6):735-42. Epub 2010 Feb 10. Pubmed

3. Cytochrome P450 2C19

Actions: substrate, inhibitor

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Li F, Wang L, Guo GL, Ma X: Metabolism-mediated drug interactions associated with ritonavir-boosted tipranavir in mice. Drug Metab Dispos. 2010 May;38(5):871-8. Epub 2010 Jan 26. Pubmed
  2. Dumond JB, Vourvahis M, Rezk NL, Patterson KB, Tien HC, White N, Jennings SH, Choi SO, Li J, Wagner MJ, La-Beck NM, Drulak M, Sabo JP, Castles MA, Macgregor TR, Kashuba AD: A phenotype-genotype approach to predicting CYP450 and P-glycoprotein drug interactions with the mixed inhibitor/inducer tipranavir/ritonavir. Clin Pharmacol Ther. 2010 Jun;87(6):735-42. Epub 2010 Feb 10. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on June 03, 2011 16:06

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.