Nelfinavir

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Nelfinavir
Nelfinavir.svg
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 cat. B (US)
Legal status -only (US)
Routes oral
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
Identifiers
CAS number 159989-64-7 YesY
ATC code J05AE04
PubChem CID 64143
DrugBank DB00220
ChemSpider 57718 YesY
UNII HO3OGH5D7I YesY
KEGG D08259 YesY
ChEMBL CHEMBL1159655 N
NIAID ChemDB 028590
Chemical data
Formula C32H45N3O4S 
Mol. mass 567.784 g/mol
Physical data
Melt. point 349.94 °C (662 °F)
 N (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 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 widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection.[1]

History[edit]

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 and elsewhere by ViiV Healthcare.

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

On the 6 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 some batches may have been contaminated with potentially cancer-causing chemicals.

Pharmacology[edit]

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

Mechanism of action[edit]

Nelfinavir is a protease inhibitor: it inhibits HIV-1 and HIV-2 proteases. HIV protease is an enzyme (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[clarification needed] between it and other PIs. Also, not all PIs inhibit both HIV-1 and HIV-2 proteases.

Toxicity[edit]

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) .

Potential anti-cancer activity[edit]

Nelfinavir were under investigation, in 2009, for potential use as an anti-cancer agent.[3] 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). [4] When Nelfinavir was given to laboratory mice with tumors of the prostate or of the brain, it could suppress tumor growth in these animals. [5][6] In vitro tests showed it may work well with sorafenib[7]

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.[8] 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).[9] 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.[10] A phase II trial of 80 patients is starting.[10]

[dated info]

Interactions[edit]

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[edit]

References[edit]

  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. PMC 90428. PMID 11257019. 
  2. ^ Press release from the European Medicines Agency regarding possible genotoxic ethyl mesylate contamination
  3. ^ 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. 
  4. ^ Gills, JJ; Lopiccolo, J; Tsurutani, J; Shoemaker, RH; Best, CJM; Abu-Asab, MS; Borojerdi, J; Warfel, NA et al. (September 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 : an Official Journal of the American Association for Cancer Research 13 (17): 5183–94. doi:10.1158/1078-0432.CCR-07-0161. PMID 17785575. 
  5. ^ 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. 
  6. ^ Yang, Y; Ikezoe, T; Takeuchi, T; Adachi, Y; Ohtsuki, Y; Takeuchi, S; Koeffler, HP; Taguchi, H (July 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): 425–33. doi:10.1111/j.1349-7006.2005.00063.x. PMID 16053514. 
  7. ^ Brüning, A; Burger, P; Vogel, M; Gingelmaier, A; Friese, K; Burges, A (October 2010). "Nelfinavir induces mitochondria protection by ERK1/2-mediated mcl-1 stabilization that can be overcome by sorafenib". Investigational New Drugs 28 (5): 535–42. doi:10.1007/s10637-009-9281-1. PMID 19554262. 
  8. ^ http://clinicaltrials.gov/ct2/results?term=Nelfinavir+cancer
  9. ^ Brunner, TB; Geiger, M; Grabenbauer, GG; Lang-Welzenbach, M; Mantoni, TS; Cavallaro, A; Sauer, R; Hohenberger, W; McKenna, WG (June 2008). "Phase I trial of the human immunodeficiency virus protease inhibitor nelfinavir and chemoradiation for locally advanced pancreatic cancer". Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 26 (16): 2699–706. doi:10.1200/JCO.2007.15.2355. PMID 18509182. 
  10. ^ a b "'Last year, I was dying of cancer. Now I might be cured'". The Sunday Telegraph. 28 November 2010.