Nelfinavir

Nelfinavir

File:Nelfinavir structure.svg
File:Nelfinavir ball-and-stick.png
Systematic (IUPAC) name
(3S,4aS,8aS)-N-tert-butyl-2-[(2R,3R)-2-hydroxy-3-[(3-hydroxy-2-methylphenyl)formamido]-4-(phenylsulfanyl)butyl]-decahydroisoquinoline-3-carboxamide
Clinical data
Trade names	Viracept
AHFS/Drugs.com	monograph
MedlinePlus	a697034
Licence data	US FDA:link
Pregnancy category	US: B (No risk in non-human studies)
Legal status	US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	Uncertain; increases when taking with food
Protein binding	>98%
Metabolism	Hepatic by CYP including CYP3A4 and CYP2C19
Biological half-life	3.5–5 hours
Excretion	feces (87%), urine (1–2%)
Identifiers
CAS Number	159989-64-7 Y
ATC code	J05AE04 (WHO)
PubChem	CID: 64143
DrugBank	DB00220 Y
ChemSpider	57718 Y
UNII	HO3OGH5D7I Y
KEGG	D08259 Y
ChEBI	CHEBI:7496 N
ChEMBL	CHEMBL1159655 N
NIAID ChemDB	028590
Chemical data
Formula	C32H45N3O4S
Molecular mass	567.784 g/mol
SMILES O=C(c1cccc(O)c1C)N[C@@H](CSc2ccccc2)[C@H](O)CN4[C@H](C(=O)NC(C)(C)C)C[C@@H]3CCCC[C@@H]3C4
InChI InChI=1S/C32H45N3O4S/c1-21-25(15-10-16-28(21)36)30(38)33-26(20-40-24-13-6-5-7-14-24)29(37)19-35-18-23-12-9-8-11-22(23)17-27(35)31(39)34-32(2,3)4/h5-7,10,13-16,22-23,26-27,29,36-37H,8-9,11-12,17-20H2,1-4H3,(H,33,38)(H,34,39)/t22-,23+,26-,27-,29+/m0/s1 Y Key:QAGYKUNXZHXKMR-HKWSIXNMSA-N Y
Physical data
Melting point	349.94 °C (661.89 °F)
NY (what is this?)  (verify)

Nelfinavir (brand name Viracept) is an antiretroviral drug used in the treatment of the human immunodeficiency virus (HIV). Nelfinavir belongs to the class of drugs known as protease inhibitors (PIs) and like other PIs is almost always used in combination with other antiretroviral drugs.

Nelfinavir mesylate (Viracept, formally AG1343) is a potent and orally bioavailable human immunodeficiency virus HIV-1 protease inhibitor (Ki=2nM) and is widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection.

History

Nelfinavir was developed by Agouron Pharmaceuticals as part of a joint venture with Eli Lilly and Company. Agouron Pharmaceuticals was acquired by Warner Lambert in 1999 and is now a subsidiary of Pfizer. It is marketed in Europe by Hoffman-La Roche and elsewhere by ViiV Healthcare.

The U.S. Food and Drug Administration (FDA) approved it for therapeutic use on March 14, 1997, making it the twelfth approved antiretroviral. The initial product launched proved to be the largest "biotech launch" in the history of the pharmaceutical industry, achieving first full year sales exceeding $US335M. Agouron's patent on the drug will expire in 2014.

On the 6 June 2007, both the Medicines and Healthcare products Regulatory Agency and the European Medicines Agency put out an alert requesting the recall of any of the drug in circulation, because some batches may have been contaminated with potentially cancer-causing chemicals.

Pharmacology

Nelfinavir should be taken with food. The bioavailability of Nelfinavir is increased 2.5 to 5 times when taken with food. Taking the drug with food also decreases the risk of diarrhea as a side effect.

Mechanism of action

Nelfinavir is a protease inhibitor: it inhibits HIV-1 and HIV-2 proteases. HIV protease is an aspartate protease which splits viral protein molecules into smaller fragments, and it is vital to both the replication of the virus within the cell, and also to the release of mature viral particles from an infected cell. Nelfinavir is a competitive inhibitor (2 nM) which is designed to bind tightly and is not cleaved due to the presence of a hydroxyl group as opposed to a keto group in the middle amino acid residue mimic, which would be otherwise S-phenylcysteine. All protease inhibitors bind to the protease, the precise mode of binding determines how the molecule inhibits the protease. The way Nelfinavir binds the enzyme may be sufficiently unique to reduce cross-resistance between it and other PIs. Also, not all PIs inhibit both HIV-1 and HIV-2 proteases.

Toxicity

Nelfinavir can produce a range of adverse side effects. Flatulence, diarrhea or abdominal pain are common (i.e. experienced by more than one in one hundred patients). Fatigue, urination, rash, mouth ulcers or hepatitis are less frequent effects (experienced by one in one thousand to one in one hundred patients). Nephrolithiasis, arthralgia, leukopenia, pancreatitis or allergic reactions may occur, but are rare (less than one in one thousand patients) .

Other bioactivity

Potential anti-cancer activity

Nelfinavir was under investigation, in 2009, for potential use as an anti-cancer agent. When applied to cancer cells in culture (in vitro), it can inhibit the growth of a variety cancer types and can trigger cell death (apoptosis). When Nelfinavir was given to laboratory mice with tumors of the prostate or of the brain, it could suppress tumor growth in these animals. In vitro tests showed it may work well with sorafenib

In the United States, several clinical trials were conducted in 2008 that sought to verify whether nelfinavir is effective as a cancer therapeutic agent in humans. In some of these trials, nelfinavir was used alone in monotherapy fashion, whereas in others it was combined with other modes of cancer therapy, such as well-established chemotherapeutic agents or radiation therapy.

In 2008 very good phase I results were obtained for locally advanced pancreatic ductal adenocarcinoma (a form of pancreatic cancer). The phase I trial (of nelfinavir with radiotherapy), on 12 patients with inoperable pancreatic cancer, showed a doubling of survival times, and six patients had tumor regression to the extent that they became operable. A phase II trial of 80 patients is starting.

Nelfinavir has many effects that inhibit cancers.

Anti-virulence activity

Nelfinavir and simple derivatives have been found to inhibit the production of the virulence factor streptolysin S, a cytolysin produced by the human pathogen Streptococcus pyogenes. Nelfinavir and these related molecules did not exhibit detectable antibiotic activity, but did also inhibit the production of other biologically active molecules, including plantazolicin (antibiotic), listeriolysin S (cytolysin), and clostridiolysin S (cytolysin), by other bacteria.

Interactions

Nelfinavir's interaction profile is similar to that of other protease inhibitors. Most interactions occur at the level of the Cytochrome P450 isozymes 3A4 and CYP2C19, by which nelfinavir is metabolised.

Synthesis

File:Nelfinavir synthesis.png

Nelfinavir synthesis:

See also

• HIV-1 protease
• Cremophor EL
• Castor oil
• Saquinavir (same perhydroisoquinoline core).