Nelfinavir

Nelfinavir

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 Y
ATC code	J05AE04
PubChem	CID 64143
DrugBank	APRD00003
ChemSpider	57718 Y
UNII	HO3OGH5D7I Y
KEGG	D08259 Y
ChEMBL	CHEMBL1159655 N
Chemical data
Formula	C32H45N3O4S
Mol. mass	567.784 g/mol
SMILES	eMolecules & PubChem
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
Melt. point	349.94 °C (662 °F)
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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^[when?] being widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection.^[1]

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 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 $335M US.^{[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 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.^{[citation needed]} 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^[when?] under investigation for potential use as an anti-cancer agent.^[3] 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).

^[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, there are several clinical trials currently^[when?] going on that seek to verify whether nelfinavir is effective as a cancer therapeutic agent in humans.^[8] 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.

Good phase I results were obtained for locally advanced pancreatic cancer.^[9]

In the UK, a phase I trial (of nelfinavir with radiotherapy) on patients with inoperable cancer showed a doubling of survival times, and six patients had tumor regression to the extent that they became operable.^[10]

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

• HIV-1 protease
• Cremophor EL
• Castor oil

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. PMC 90428. PMID 11257019. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=90428. 
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. http://clincancerres.aacrjournals.org/content/13/17/5183.full.pdf+html. 
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 et al. (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. http://jco.ascopubs.org/content/26/16/2699.full.pdf. 
10. ^ "'Last year, I was dying of cancer. Now I might be cured'". The Sunday Telegraph. 28 November 2010. http://www.telegraph.co.uk/news/telegraphchristmasappeal/8164996/Telegraph-Christmas-Appeal-Last-year-I-was-dying-of-cancer.-Now-I-might-be-cured.html. 

• Pai, VB; Nahata, MC (March 1999). "Nelfinavir mesylate: a protease inhibitor". The Annals of Pharmacotherapy 33 (3): 325–39. doi:10.1345/aph.18089. PMID 10200859. 
• Bardsley-Elliot, A; Plosker, GL (March 2000). "Nelfinavir: an update on its use in HIV infection". Drugs 59 (3): 581–620. doi:10.2165/00003495-200059030-00014. PMID 10776836. 
• Actual photo of Nelfinavir and further Nelfinavir information