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Indinavir

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Indinavir
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Systematic (IUPAC) name
(2S)-1-[(2S,4R)-4-benzyl-2-hydroxy-4-{[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamoyl}butyl]-N-tert-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide
Clinical data
Trade names Crixivan
AHFS/Drugs.com monograph
MedlinePlus a696028
Licence data US FDA:link
  • US: C (Risk not ruled out)
Oral
Pharmacokinetic data
Bioavailability ~65%
Protein binding 60%
Metabolism Hepatic via CYP3A4
Half-life 1.8 (± 0.4) hours
Identifiers
150378-17-9 7pxY
J05AE02
PubChem CID 5362440
DrugBank DB00224 7pxY
ChemSpider 4515036 7pxY
UNII 9MG78X43ZT 7pxY
KEGG C07051 7pxY
ChEBI CHEBI:44032 7pxY
ChEMBL CHEMBL540914 7pxN
NIAID ChemDB 005824
PDB ligand ID MK1 (PDBe, RCSB PDB)
Chemical data
Formula C36H47N5O4
613.79 g/mol
 14pxN (what is this?)  (verify)

Indinavir (IDV; trade name Crixivan, manufactured by Merck) is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS.

File:2avo Indinavir.png
HIV-1 protease in complex with indinavir. PDB entry 2avo[1]

It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.[2]

Medical uses

Unfortunately, indinavir wears off quickly after dosing, so requires very precise dosing every eight hours to thwart HIV from forming drug-resistant mutations, including resistances to other protease inhibitors. It has restrictions on what sorts of food may be eaten concurrently. For these reasons it is now rarely used.

Side effects

The most common side effects of indinavir include:[3]

Indinavir inhibits urinary nitrous oxide production and may inhibit nitric oxide production. Treatment with this drug is frequently associated with renal abnormalities, sterile leukocyturia, and reduced creatinine clearance.[4]

Indinavir impairs endothelial function in healthy HIV-negative men and may accelerate atherosclerotic disease.[5]

History

The Food and Drug Administration approved indinavir on March 13, 1996, making it the eighth approved antiretroviral. Indinavir is much more powerful than any prior antiretroviral drug; using it with dual NRTIs set the standard for treatment of HIV/AIDS and raised the bar on design and introduction of subsequent antiretroviral drugs. Protease inhibitors changed the very nature of the AIDS epidemic from one of a terminal illness to a somewhat manageable one.

Increasingly, it is being replaced by newer drugs that are more convenient to take and less likely to promote virus resistance, such as lopinavir or atazanavir.

Synthesis

File:Indinavir synthesis.png
Indinavir synthesis:[6]

References

  1. Liu, F.; Boross, P. I.; Wang, Y. F.; Tozser, J.; Louis, J. M.; Harrison, R. W.; Weber, I. T. (2005). "Kinetic, Stability, and Structural Changes in High-resolution Crystal Structures of HIV-1 Protease with Drug-resistant Mutations L24I, I50V, and G73S". Journal of Molecular Biology 354 (4): 789–800. PMC 1403828. PMID 16277992. doi:10.1016/j.jmb.2005.09.095.  edit
  2. "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  3. "Crixivan® (indinavir sulfate) Capsules. Prescribing Information. Revised December 2013" (PDF). Merck & Co., Inc. Retrieved 6 February 2014. 
  4. M. Eira, M. Araujo and A.C. Seguro. Urinary NO3 excretion and renal failure in indinavir-treated patients. Brazilian Journal of Medical and Biological Research (2006) 39: 1065-1070.
  5. Shankar SS, Dubé MP, Gorski JC, Klaunig JE, Steinberg HO. Indinavir impairs endothelial function in healthy HIV-negative men. Am Heart J. 2005 Nov;150(5):933.
  6. Askin, D.; Eng, K. K.; Rossen, K.; Purick, R. M.; Wells, K. M.; Volante, R. P.; Reider, P. J. (1994). "Highly diastereoselective reaction of a chiral, non-racemic amide enolate with (S)-glycidyl tosylate. Synthesis of the orally active HIV-1 protease inhibitor L-735,524". Tetrahedron Letters 35 (5): 673. doi:10.1016/S0040-4039(00)75787-X.  edit