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Nelfinavir
Systematic (IUPAC) name
(3S,4aS,8aS)-N-tert-butyl-2-[(2 R,3R)-2-hydroxy-3-[(3-hydroxy-2-methylphenyl)formamido]-4-(phenylsulfanyl)butyl]-decahydroisoquinoline-3-carboxamide
Identifiers
CAS number 159989-64-7
ATC code J05AE04
PubChem 64143
DrugBank APRD00003
Chemical data
Formula C 32H45N3O4S 
Mol. mass 567.784 g/mol
Physical data
Melt. point 349.94 °C (662 °F)
Pharmacokinetic data
Bioavailability Uncertain; improved by taking with food
Protein binding >98%
Metabolism Hepatic metabolism by CYP450 incl. CYP3A4
Half life 3.5 - 5 hours
Excretion Metabolites eliminated in faeces
Therapeutic considerations
Pregnancy cat.  ?
Legal status
Routes  ?
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Nelfinavir (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 generally 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 being widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection. [1]

Contents

History

Nelfinavir was developed by Agouron Pharmaceuticals as part of a joint venture with Japan Tobacco. 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. The Food and Drug Administration 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 $335M US. Agouron's patent on the drug will expire in 2014.

On the 6th June 2007 both the Medicines and Healthcare products Regulatory Agency and the European Medicines Agency[2] put out an alert requesting the recall of any of the drug in circulation because of fears that batches of the therapy 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.

Mode of action

Nelfinavir is a protease inhibitor: it inhibits HIV-1 and HIV-2 proteases. This protease is an enzyme which cleaves viral protein molecules into smaller fragments, and it is vital for both the replication of the virus within the cell and also the release of mature viral particles from an infected cell. Though this mode of action is common to all protease inhibitors, the precise mode of binding of nelfinavir to 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 effects. Common (experienced by more than one in one hundred patients; greater than 1%) are flatulence, diarrhea or abdominal pain. Infrequent (experienced by one in one thousand to one in one hundred patients; 0.01 - 0.1%) adverse effects are fatigue, urination, rash, mouth ulcers or hepatitis. Rarely (less than one in one thousand patients; under 0.01%) nephrolithiasis, arthralgia, Leukopenia, pancreatitis or allergic reactions may occur.

Potential anti-cancer activity

Nelfinavir is currently under investigation for potential use as an anti-cancer agent. When applied to cancer cells in culture (in vitro), it is able to inhibit the growth of a variety of different cancer types and triggers cell death (apoptosis).[3] When Nelfinavir was given to laboratory mice with tumors of the prostate or of the brain, it could suppress tumor growth in these animals.[4][5] Although these laboratory outcomes are promising, it has not yet convincingly been established whether such tumor therapeutic effects can also be achieved in human cancer patients.[6]

In the United States, there are several clinical trials currently going on that seek to verify whether nelfinavir is effective as a cancer therapeutic agent in humans. In some of these trials, nelfinavir is used alone in monotherapy fashion, whereas in others it is combined with other modes of cancer therapy, such as well-established chemotherapeutic agents or radiation therapy. It might take several years for most of these studies to be completed and their results published.

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.

See also

References

  1. ^ Zhang KE, Wu E, Patick AK, et al. (April 2001). "Circulating metabolites of the human immunodeficiency virus protease inhibitor nelfinavir in humans: structural identification, levels in plasma, and antiviral activities". Antimicrob. Agents Chemother. 45 (4): 1086–93. doi:10.1128/AAC.45.4.1086-1093.2001. PMID 11257019.  
  2. ^ Press release from the European Medicines Agency regarding possible genotoxic ethyl mesylate contamination
  3. ^ J.J. Gills et al. (2007). "Nelfinavir, A Lead HIV Protease Inhibitor, Is a Broad-Spectrum, Anticancer Agent that Induces Endoplasmic Reticulum Stress, Autophagy, and Apoptosis In vitro and In vivo". Clinical Cancer Research 13 (17): 5183–5194. doi:10.1158/1078-0432.CCR-07-0161. PMID 17785575. http://clincancerres.aacrjournals.org/cgi/content/abstract/13/17/5183.  
  4. ^ Pyrko, P.; Kardosh, A; Wang, W; Xiong, W; Schönthal, AH; Chen, TC (2007). "HIV-1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress". Cancer Research 67 (22): 10920–10928. doi:10.1158/0008-5472.CAN-07-0796. PMID 18006837.  
  5. ^ Yang, Yang; Ikezoe, T; Takeuchi, T; Adachi, Y; Ohtsuki, Y; Takeuchi, S; Koeffler, HP; Taguchi, H (2005). "HIV-1 protease inhibitor induces growth arrest and apoptosis of human prostate cancer LNCaP cells in vitro and in vivo in conjunction with blockade of androgen receptor STAT3 and AKT signaling.". Cancer Science 96 (7): 425–433. doi:10.1111/j.1349-7006.2005.00063.x. PMID 16053514. http://www.ncbi.nlm.nih.gov/pubmed/16053514.  
  6. ^ Chow WA, Jiang C, Guan M (2009). "Anti-HIV drugs for cancer therapeutics: back to the future?". Lancet Oncol 10 (1): 61–71. doi:10.1016/S1470-2045(08)70334-6. PMID 19111246.  







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