It07:Indinavir

Indinavir

Indinavir
General
Systematic name
Molecular formula	C36H47N5O4
SMILES
Molar mass	613.79 g mol-1
CAS number
Properties
Density & phase	solid
Melting point
Boiling point
Chiral rotation [α]D
Hazards
MSDS	http://www.sigmaaldrich.com/
Main hazards
Supplementary data page
Structure and properties	n, εr, etc.
Thermodynamic data	Phase behaviour Solid, liquid, gas
Spectral data	UV, IR, NMR, MS
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox disclaimer and references

Indinavir (Crixivan®, Merck) is a protease inhibitor used in combination therapy of human immunodeficiency virus (HIV) infection. It was discovered in Merck Research Laboratories at West Point, PA in January 1992 as part of Merck’s search for an HIV protease inhibitor. Clinical trials took another four years, and on March 14, 1996, the drug received fast-track FDA clearance after a mere 42 days of Merck having filed the application.

|

Oxazaborolidineplusalkynyl

Mechanism of action

The biological target of indinavir is the HIV-encoded protease. This enzyme is a dimer of a 99-amino-acid protein and has aspartyl protease activity typical of retroviral proteases. It catalyzes the cleavage of a number of amino acid sequences on the viral envelope just as the viral particle buds from the host cell membrane, and the generation of new functional viral particles is dependent on this process. Thus, the key is that HIV with an inhibited protease cannot create infectious virions so that infection is kept at bay.

Indinavir is a competitive inhibitor of HIV protease and prevents the cleavage of these amino acid sequences and thus puts a stop to the maturation of new virions. The molecule contains a synthetic analogue of the phenylalanine-proline sequence which is cleaved by the protease, but as it binds much more strongly to the protease, the enzyme is inhibited. Thus, immature and non-infectious virions are produced. Thus, indinavir does not affect cells which have already been infected; it only prevents infection of more cells. The IC50 (in-vitro concentration required to reduce viral production by 50%) ranges from 2 to 60 nM. Human aspartyl proteases such as renin and pepsin are not affected by indinavir as their IC50 is several orders of magnitude higher.

Side Effects

Like all protease inhibitors, indinavir has gastrointestinal side effects: The drug causes nausea, vomiting and diarrhea, which can make adherence to a treatment regimen rather difficult. It has also been reported to lead to high serum aminotransferase concentrations as well as hyperlipidemia, glucose intolerance and abnormal fat distribution. By far the most significant (and dose-limiting) side effect is that of nephrolithiasis (formation of kidney stones). This is partly a consequence of the low solubility of indinavir in water, which can lead to crystals of indinavir being deposited in renal tubules.

Synthesis

The chemical synthesis of crixivan posed an enormous challenge to process chemists. The molecule has five chiral centres (and thus 32 possible stereoisomers) and approximately 1 kg is needed per patient per year, which makes it one of the most complex molecules ever made in metric ton quantities. During development, it took Merck’s chemists six weeks to synthesize one batch of material.

Clinical Antiviral Activity

The therapy with HIV protease inhibitors was reviewed by Charles Flexner in 1998. Indinavir monotherapy (no other antiretroviral medication given) reduces the patient’s viral load significantly within a few days after the start of treatment. Plasma HIV RNA concentrations are reduced by a factor of 100 to 1000, with a concomitant increase in CD4+ cells of 100 to 150 cells per cubic millimetre. A relatively large dose of 2.4 g per day is required to achieve this effect. However, treatment of HIV infection with only one antiretroviral drug is not recommended and is even dangerous, as the virus can develop primary as well as secondary resistance to indinavir. “Secondary resistance” means that the virus is not only resistant to indinavir but also to other protease inhibitors that it has never encountered before.

This has led to the concept of combination therapy, in which one protease inhibitor, e.g. indinavir, is administered alongside two other drugs such as nucleoside analogues: in 60% of patients, the combination of indinavir with zidovudine and lamivudine reduces the viral load to undetectable levels, which is less than 50 copies of HIV RNA per cubic millimetre, for 2 years. This is illustrates the major improvements that have become possible through the invention of protease inhibitors in the therapy of HIV infection. A cocktail of three or four drugs is much more effective than a single drug, not least because it is very unlikely that the virus develops resistance against all three medications.