Chemistry:Nelfinavir

From HandWiki
Short description: Antiretroviral drug
Nelfinavir
Nelfinavir structure.svg
Nelfinavir ball-and-stick.png
Clinical data
Trade namesViracept
Other namesNFV
AHFS/Drugs.comMonograph
MedlinePlusa697034
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityUncertain; increases when taking with food[1]
Protein binding>98%
MetabolismLiver by CYP including CYP3A4 and CYP2C19
Elimination half-life3.5–5 hours
Excretionfeces (87%), urine (1–2%)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
Chemical and physical data
FormulaC32H45N3O4S
Molar mass567.79 g·mol−1
3D model (JSmol)
Melting point349.94 °C (661.89 °F)
 ☒N☑Y (what is this?)  (verify)

Nelfinavir, sold under the brand name Viracept, is an antiretroviral medication used in the treatment of HIV/AIDS. 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 is an orally bioavailable human immunodeficiency virus HIV-1 protease inhibitor (Ki = 2 nM) and is widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection.[2]

It was patented in 1992 and approved for medical use in 1997.[3]

Toxicity

Common (>1%) side effects include insulin resistance, hyperglycemia and lipodystrophy.[4]

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

Antiviral

Nelfinavir inhibits maturation and export of the herpes simplex 1 virus[5] and the Kaposi's sarcoma virus.[6]

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.[7] 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.[7]

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.

Pharmacology

Nelfinavir should be taken with food. Taking the drug with food 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[4] (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.

History

Nelfinavir was developed by Agouron Pharmaceuticals as part of a joint venture with Eli Lilly and Company.[8] 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.[citation needed]

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 expired in 2014.

On the 6 June 2007, both the Medicines and Healthcare products Regulatory Agency and the European Medicines Agency[9] 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.

Research

Since 2009, nelfinavir has been under investigation for potential use as an anti-cancer agent.[10] When applied to cancer cells in culture (in vitro), it can inhibit the growth of a variety of cancer types and can trigger cell death (apoptosis).[11] When Nelfinavir was given to laboratory mice with tumors of the prostate or of the brain, it could suppress tumor growth in these animals.[12][13] At the cellular level, nelfinavir exerts multiple effects to inhibit cancer growth; the two main ones appear to be inhibition of the Akt/PKB signaling pathway and activation of endoplasmic reticulum stress with subsequent unfolded protein response.[14]

In the United States, about three dozen clinical trials are being conducted (or have been completed) in order to determine whether nelfinavir is effective as a cancer therapeutic agent in humans.[15] 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.[citation needed]

(As of April 2022), nelfinavir is being studied as a radiosensitizing agent as part of treatment of advanced cervical cancer.[16]

References

  1. ↑ "Viracept (nelfinavir mesylate) Tablets and Oral Powder, for Oral Use. Full Prescribing Information". ViiV Healthcare Company. Research Triangle Park, NC 27709. https://www.viivhealthcare.com/media/32259/us_viracept.pdf. 
  2. ↑ "Circulating metabolites of the human immunodeficiency virus protease inhibitor nelfinavir in humans: structural identification, levels in plasma, and antiviral activities". Antimicrobial Agents and Chemotherapy 45 (4): 1086–1093. April 2001. doi:10.1128/AAC.45.4.1086-1093.2001. PMID 11257019. 
  3. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 510. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA510. 
  4. ↑ 4.0 4.1 "Recent advances in drug repositioning for the discovery of new anticancer drugs". International Journal of Biological Sciences 10 (7): 654–663. 2014. doi:10.7150/ijbs.9224. PMID 25013375. 
  5. ↑ "Nelfinavir inhibits maturation and export of herpes simplex virus 1". Journal of Virology 88 (10): 5455–5461. May 2014. doi:10.1128/JVI.03790-13. PMID 24574416. 
  6. ↑ "The HIV protease inhibitor nelfinavir inhibits Kaposi's sarcoma-associated herpesvirus replication in vitro". Antimicrobial Agents and Chemotherapy 55 (6): 2696–2703. June 2011. doi:10.1128/AAC.01295-10. PMID 21402841. 
  7. ↑ 7.0 7.1 "HIV protease inhibitors block streptolysin S production". ACS Chemical Biology 10 (5): 1217–1226. May 2015. doi:10.1021/cb500843r. PMID 25668590. 
  8. ↑ "Viracept (nelfinavir mesylate, AG1343): a potent, orally bioavailable inhibitor of HIV-1 protease". Journal of Medicinal Chemistry 40 (24): 3979–3985. November 1997. doi:10.1021/jm9704098. PMID 9397180. 
  9. ↑ Press release from the European Medicines Agency regarding possible genotoxic ethyl mesylate contamination
  10. ↑ "Anti-HIV drugs for cancer therapeutics: back to the future?". The Lancet. Oncology 10 (1): 61–71. January 2009. doi:10.1016/S1470-2045(08)70334-6. PMID 19111246. 
  11. ↑ "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. September 2007. doi:10.1158/1078-0432.CCR-07-0161. PMID 17785575. 
  12. ↑ "HIV-1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress". Cancer Research 67 (22): 10920–10928. November 2007. doi:10.1158/0008-5472.CAN-07-0796. PMID 18006837. 
  13. ↑ "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. July 2005. doi:10.1111/j.1349-7006.2005.00063.x. PMID 16053514. 
  14. ↑ "Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity". F1000Research 4 (2): 9. 2015. doi:10.12688/f1000research.5827.2. PMID 26097685. 
  15. ↑ "Search of: Nelfinavir cancer - List Results - ClinicalTrials.gov". https://clinicaltrials.gov/ct2/results?term=Nelfinavir+cancer. 
  16. ↑ Clinical trial number NCT03256916 for "A Phase III Randomized Clinical Trial to Study the Radiosensitizing Effect of Nelfinavir in Locally Advanced Carcinoma of Uterine Cervix." at ClinicalTrials.gov

Further reading

External links



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Nelfinavir&oldid=3326197"