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Identification
Name Atazanavir
Accession Number DB01072 (APRD00804)
Type small molecule
Groups approved
Description

Atazanavir (formerly known as BMS-232632) is an antiretroviral drug of the protease inhibitor (PI) class. Like other antiretrovirals, it is used to treat infection of human immunodeficiency virus (HIV). Atazanavir is distinguished from other PIs in that it can be given once-daily (rather than requiring multiple doses per day) and has lesser effects on the patient’s lipid profile (the amounts of cholesterol and other fatty substances in the blood). Like other protease inhibitors, it is used only in combination with other HIV medications. The U.S. Food and Drug Administration (FDA) approved atazanavir on June 20, 2003. [Wikipedia]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • atazanavir
  • Atazanavir sulfate
  • ATV
  • ATZ
  • BMS-232632
Brand names
  • Latazanavir
  • Reyataz
  • Zrivada
Brand name mixtures Not Available
Categories
  • Anti-HIV Agents
  • Protease Inhibitors
  • HIV Protease Inhibitors
CAS number 198904-31-3
Weight Average: 704.8555
Monoisotopic: 704.389748048
Chemical Formula C38H52N6O7
InChI Key InChIKey=AXRYRYVKAWYZBR-GASGPIRDSA-N
InChI
InChI=1S/C38H52N6O7/c1-37(2,3)31(41-35(48)50-7)33(46)40-29(22-25-14-10-9-11-15-25)30(45)24-44(43-34(47)32(38(4,5)6)42-36(49)51-8)23-26-17-19-27(20-18-26)28-16-12-13-21-39-28/h9-21,29-32,45H,22-24H2,1-8H3,(H,40,46)(H,41,48)(H,42,49)(H,43,47)/t29-,30-,31+,32+/m0/s1
Plain Text
IUPAC Name
methyl N-[(1S)-1-{N'-[(2S,3S)-2-hydroxy-3-[(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanamido]-4-phenylbutyl]-N'-{[4-(pyridin-2-yl)phenyl]methyl}hydrazinecarbonyl}-2,2-dimethylpropyl]carbamate
SMILES
COC(=O)N[C@H](C(=O)N[C@@H](CC1=CC=CC=C1)[C@@H](O)CN(CC1=CC=C(C=C1)C1=NC=CC=C1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phenethylamines
  • Polypeptides
  • Amphetamines
Substructures
  • Hydroxy Compounds
  • Carboxylic Acids and Derivatives
  • Carbamates and Derivatives
  • Amino Ketones
  • Pyridines and Derivatives
  • Ethers
  • Benzene and Derivatives
  • Phenethylamines
  • Polypeptides
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Hydrazine Derivatives
  • Imines
  • Alcohols and Polyols
  • Amphetamines
Pharmacology
Indication Used in combination with other antiretroviral agents for the treatment of HIV-1 infection, as well as postexposure prophylaxis of HIV infection in individuals who have had occupational or nonoccupational exposure to potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission.
Pharmacodynamics Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). 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. Atazanavir 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. Atazanivir is pharmacologically related but structurally different from other protease inhibitors and other currently available antiretrovirals.
Mechanism of action Atazanavir selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells by binding to the active site of HIV-1 protease, thus preventing the formation of mature virions. Atazanavir is not active against HIV-2.
Absorption Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Oral bioavailability is 60-68%.
Volume of distribution Not Available
Protein binding 86% bound to human serum proteins (alpha-1-acid glycoprotein and albumin). Protein binding is independent of concentration.
Metabolism

Atazanavir is extensively metabolized in humans, primarily by the liver. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A.
Route of elimination Not Available
Half life Elimination half-life in adults (healthy and HIV infected) is approximately 7 hours (following a 400 mg daily dose with a light meal). Elimination half-life in hepatically impaired is 12.1 hours (following a single 400 mg dose).
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Human Immunodeficiency Virus
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Bristol myers squibb co
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Prices
Unit description Cost Unit
Reyataz 300 mg capsule 36.63 USD capsule
Reyataz 150 mg capsule 18.49 USD capsule
Reyataz 200 mg capsule 18.49 USD capsule
Reyataz 100 mg capsule 18.12 USD capsule
Patents
Country Patent Number Approved Expires
United States 6087383 1998-12-21 2018-12-21
United States 5849911 1997-06-20 2017-06-20
Canada 2250840 2006-07-04 2017-04-14
Canada 2317736 2004-11-02 2018-12-22
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility Free base slightly soluble (4-5 mg/mL) PhysProp
logP 4.5 PhysProp
Predicted Properties
Property Value Source
water solubility 3.27e-03 g/l ALOGPS
logP 4.08 ALOGPS
logP 4.54 ChemAxon Molconvert
logS -5.33 ALOGPS
pKa 13.07 ChemAxon Molconvert
hydrogen acceptor count 7 ChemAxon Molconvert
hydrogen donor count 5 ChemAxon Molconvert
polar surface area 171.22 ChemAxon Molconvert
rotatable bond count 18 ChemAxon Molconvert
refractivity 191.80 ChemAxon Molconvert
polarizability 76.83 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Croom KF, Dhillon S, Keam SJ: Atazanavir: a review of its use in the management of HIV-1 infection. Drugs. 2009 May 29;69(8):1107-40. doi: 10.2165/00003495-200969080-00009. Pubmed
  2. von Hentig N: Atazanavir/ritonavir: a review of its use in HIV therapy. Drugs Today (Barc). 2008 Feb;44(2):103-32. Pubmed
  3. Swainston Harrison T, Scott LJ: Atazanavir: a review of its use in the management of HIV infection. Drugs. 2005;65(16):2309-36. Pubmed
  4. Le Tiec C, Barrail A, Goujard C, Taburet AM: Clinical pharmacokinetics and summary of efficacy and tolerability of atazanavir. Clin Pharmacokinet. 2005;44(10):1035-50. Pubmed
  5. Lopez-Cortes LF: [Pharmacology, pharmacokinetic features and interactions of atazanavir] Enferm Infecc Microbiol Clin. 2008 Dec;26 Suppl 17:2-8. Pubmed
  6. Busti AJ, Hall RG, Margolis DM: Atazanavir for the treatment of human immunodeficiency virus infection. Pharmacotherapy. 2004 Dec;24(12):1732-47. Pubmed
External Links
Resource Link
KEGG Drug D01276 Link_out
PubChem Compound 148192 Link_out
PubChem Substance 46508504 Link_out
ChemSpider 130642 Link_out
BindingDB 13934 Link_out
ChEBI 37924 Link_out
ChEMBL 37924 Link_out
Therapeutic Targets Database DNC000332 Link_out
PharmGKB PA10251 Link_out
Drug Product Database 2248610 Link_out
RxList http://www.rxlist.com/cgi/generic/reyataz.htm Link_out
Drugs.com http://www.drugs.com/cdi/atazanavir.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/rey1671.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Atazanavir Link_out
ATC Codes
  • J05AE08
AHFS Codes
  • 08:18.08.08
PDB Entries Not Available
FDA label show (411.6 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions
  • Administration with food reduces pharmacokinetic variability.
  • Food increases product absorption.
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. Dandache S, Sevigny G, Yelle J, Stranix BR, Parkin N, Schapiro JM, Wainberg MA, Wu JJ: In Vitro Antiviral Activity and Cross-Resistance Profile of PL-100, a Next Generation Protease Inhibitor of Human Immunodeficiency Virus Type 1. Antimicrob Agents Chemother. 2007 Jul 16;. Pubmed
  5. Wood R: Atazanavir: its role in HIV treatment. Expert Rev Anti Infect Ther. 2008 Dec;6(6):785-96. Pubmed
  6. Le Tiec C, Barrail A, Goujard C, Taburet AM: Clinical pharmacokinetics and summary of efficacy and tolerability of atazanavir. Clin Pharmacokinet. 2005;44(10):1035-50. Pubmed
  7. Pyrko P, Kardosh A, Wang W, Xiong W, Schonthal AH, Chen TC: HIV-1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress. Cancer Res. 2007 Nov 15;67(22):10920-8. Pubmed
  8. Menendez-Arias L, Tozser J: HIV-1 protease inhibitors: effects on HIV-2 replication and resistance. Trends Pharmacol Sci. 2008 Jan;29(1):42-9. Epub 2007 Dec 4. Pubmed
  9. Lopez-Cortes LF: [Pharmacology, pharmacokinetic features and interactions of atazanavir] Enferm Infecc Microbiol Clin. 2008 Dec;26 Suppl 17:2-8. Pubmed
  10. Busti AJ, Hall RG, Margolis DM: Atazanavir for the treatment of human immunodeficiency virus infection. Pharmacotherapy. 2004 Dec;24(12):1732-47. 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. Le Tiec C, Barrail A, Goujard C, Taburet AM: Clinical pharmacokinetics and summary of efficacy and tolerability of atazanavir. Clin Pharmacokinet. 2005;44(10):1035-50. Pubmed
  2. Busti AJ, Hall RG, Margolis DM: Atazanavir for the treatment of human immunodeficiency virus infection. Pharmacotherapy. 2004 Dec;24(12):1732-47. Pubmed
  3. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

2. Cytochrome P450 2C9

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Busti AJ, Hall RG, Margolis DM: Atazanavir for the treatment of human immunodeficiency virus infection. Pharmacotherapy. 2004 Dec;24(12):1732-47. Pubmed
Transporters

1. Multidrug resistance protein 1

Actions: substrate, inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Perloff ES, Duan SX, Skolnik PR, Greenblatt DJ, von Moltke LL: Atazanavir: effects on P-glycoprotein transport and CYP3A metabolism in vitro. Drug Metab Dispos. 2005 Jun;33(6):764-70. Epub 2005 Mar 11. Pubmed
  2. Lucia MB, Golotta C, Rutella S, Rastrelli E, Savarino A, Cauda R: Atazanavir inhibits P-glycoprotein and multidrug resistance-associated protein efflux activity. J Acquir Immune Defic Syndr. 2005 Aug 15;39(5):635-7. Pubmed
  3. Chinn LW, Gow JM, Tse MM, Becker SL, Kroetz DL: Interindividual variability in the effect of atazanavir and saquinavir on the expression of lymphocyte P-glycoprotein. J Antimicrob Chemother. 2007 Jul;60(1):61-7. Epub 2007 May 17. Pubmed
  4. Wood R: Atazanavir: its role in HIV treatment. Expert Rev Anti Infect Ther. 2008 Dec;6(6):785-96. Pubmed
  5. Janneh O, Anwar T, Jungbauer C, Kopp S, Khoo SH, Back DJ, Chiba P: P-glycoprotein, multidrug resistance-associated proteins and human organic anion transporting polypeptide influence the intracellular accumulation of atazanavir. Antivir Ther. 2009;14(7):965-74. Pubmed
  6. Storch CH, Theile D, Lindenmaier H, Haefeli WE, Weiss J: Comparison of the inhibitory activity of anti-HIV drugs on P-glycoprotein. Biochem Pharmacol. 2007 May 15;73(10):1573-81. Epub 2007 Jan 24. Pubmed

2. Multidrug resistance-associated protein 1

Actions: substrate, inhibitor

May participate directly in the active transport of drugs into subcellular organelles or influence drug distribution indirectly. Confers resistance to anticancer drugs. Transports LTC4. May protect milk against xenobiotics

UniProt ID: P33527 Link_out
Gene: ABCC1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Janneh O, Anwar T, Jungbauer C, Kopp S, Khoo SH, Back DJ, Chiba P: P-glycoprotein, multidrug resistance-associated proteins and human organic anion transporting polypeptide influence the intracellular accumulation of atazanavir. Antivir Ther. 2009;14(7):965-74. Pubmed
  2. Lucia MB, Golotta C, Rutella S, Rastrelli E, Savarino A, Cauda R: Atazanavir inhibits P-glycoprotein and multidrug resistance-associated protein efflux activity. J Acquir Immune Defic Syndr. 2005 Aug 15;39(5):635-7. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:08

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.