Indinavir

Indinavir

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
Pregnancy cat.	C (US)
Legal status	?
Routes	Oral
Pharmacokinetic data
Protein binding	60%
Metabolism	Hepatic via CYP3A4
Half-life	1.8 (± 0.4) hours
Identifiers
CAS number	150378-17-9 Y
ATC code	J05AE02
PubChem	CID 5362440
DrugBank	DB00224
ChemSpider	4515036 Y
UNII	9MG78X43ZT Y
KEGG	C07051 Y
ChEBI	CHEBI:44032 Y
ChEMBL	CHEMBL540914 N
NIAID ChemDB	005824
Chemical data
Formula	C36H47N5O4
Mol. mass	613.79 g/mol
SMILES CC(C)(C)NC(=O)[C@@H]1CN(CCN1C[C@H](C[C@@H](Cc2ccccc2)C(=O)N[C@H]3c4ccccc4C[C@H]3O)O)Cc5cccnc5
InChI InChI=1S/C36H47N5O4/c1-36(2,3)39-35(45)31-24-40(22-26-12-9-15-37-21-26)16-17-41(31)23-29(42)19-28(18-25-10-5-4-6-11-25)34(44)38-33-30-14-8-7-13-27(30)20-32(33)43/h4-15,21,28-29,31-33,42-43H,16-20,22-24H2,1-3H3,(H,38,44)(H,39,45)/t28-,29+,31+,32-,33+/m1/s1 Y Key:CBVCZFGXHXORBI-PXQQMZJSSA-N Y
N (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 (HAART) to treat HIV infection and AIDS.

HIV-1 protease in complex with Indinavir. PDB entry 2avo

History

The Food and Drug Administration (FDA) approved indinavir March 13, 1996, making it the eighth approved antiretroviral. Indinavir was 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 resistant virus, such as lopinavir or atazanavir.

Administration

Unfortunately, indinavir wears off quickly after dosing and therefore requires dosing very precisely every eight hours in order 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.

Side effects

Most common side effects of indinavir include:

• General malaise and fatigue;
• Kidney stones, which sometimes may lead to more severe condition including kidney failure;
• Metabolic alterations including hyperlipidemia (cholesterol or triglyceride elevations) and hyperglycemia;
• Alterations in body shape (lipodystrophy), colloquially known as "Crix belly"

Endothelial cells produce nitric oxide (NO) which causes blood vessels to dilate, lowers blood pressure, allows oxygen to reach and nutrients to reach tissues, and allows carbon dioxide and metabolic waste to be removed. Nitric oxide is highly reactive and quickly reacts with molecular oxygen (O₂) to form nitrogen dioxide (NO₂).

2NO + O₂ → 2NO₂

A further reaction between nitrogen dioxide (NO₂) and water (H₂O) can produce nitrate (NO₃). The nitrate is then removed from the body in the urine. The kidney is filled with small blood vessels. In the absence of nitric oxide, these blood vessels may become constricted, and the kidney may become ischemic, leading to kidney disease.

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.

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

External links

• Indinavir bound to proteins in the PDB