Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Nelfinavir: Difference between pages

{{Short description|Antiretroviral drug}}

{{Use dmy dates|date=March 2024}}

| verifiedrevid = 462259026

| image = Nelfinavir structure.svg

| alt =

| image2 = Nelfinavir ball-and-stick.png

| alt2 =

<!-- Clinical data -->

| DailyMedID = Nelfinavir

| routes_of_administration = [[Oral administration|By mouth]]

| ATC_prefix = J05

| ATC_suffix = AE04

<!-- Pharmacokinetic data -->

| bioavailability = Uncertain; increases when taking with food<ref>{{cite web|title=Viracept (nelfinavir mesylate) Tablets and Oral Powder, for Oral Use. Full Prescribing Information|url=https://www.viivhealthcare.com/media/32259/us_viracept.pdf|publisher=ViiV Healthcare Company. Research Triangle Park, NC 27709|access-date=23 November 2015}}</ref>

| metabolism = Liver by [[Cytochrome P450|CYP]] including [[CYP3A4]] and [[CYP2C19]]

| elimination_half-life = 3.5–5 hours

| excretion = feces (87%), urine (1–2%)

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 7496

| ChEMBL = 1159655

| NIAID_ChemDB = 028590

| synonyms = NFV

<!--Chemical data-->

| IUPAC_name = (3''S'',4a''S'',8a''S'')-''N-tert''-butyl-2-[(2''R'',3''R'')-2-hydroxy-3-[(3-hydroxy-2-methylphenyl)formamido]-4-(phenylsulfanyl)butyl]-decahydroisoquinoline-3-carboxamide

| C=32 | H=45 | N=3 | O=4 | S=1

<!-- Definition and medical uses -->

'''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 inhibitor (pharmacology)|protease inhibitors]] (PIs) and like other PIs is almost always used in combination with other antiretroviral drugs.

<!-- Side effects and mechanisms -->

Nelfinavir is an orally bioavailable human immunodeficiency virus [[HIV-1 protease]] inhibitor (K_i = 2 nM) and is widely prescribed in combination with [[HIV]] reverse transcriptase inhibitors for the treatment of HIV infection.<ref>{{cite journal | vauthors = Zhang KE, Wu E, Patick AK, Kerr B, Zorbas M, Lankford A, Kobayashi T, Maeda Y, Shetty B, Webber S | display-authors = 6 | title = Circulating metabolites of the human immunodeficiency virus protease inhibitor nelfinavir in humans: structural identification, levels in plasma, and antiviral activities | journal = Antimicrobial Agents and Chemotherapy | volume = 45 | issue = 4 | pages = 1086–1093 | date = April 2001 | pmid = 11257019 | pmc = 90428 | doi = 10.1128/AAC.45.4.1086-1093.2001 }}</ref>

<!-- Society and culture -->

It was patented in 1992 and approved for medical use in 1997.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=510 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA510 |language=en}}</ref>

== Toxicity ==

Common (>1%) side effects include [[insulin resistance]], [[hyperglycemia]] and [[lipodystrophy]].<ref name=Shim2014/>

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 ulcer]]s, or [[hepatitis]] are less frequent effects (experienced by one in one thousand to one in one hundred patients). [[Nephrolithiasis]], [[arthralgia]], [[leukopenia]], [[pancreatitis]], or [[allergy|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]]<ref>{{cite journal | vauthors = Kalu NN, Desai PJ, Shirley CM, Gibson W, Dennis PA, Ambinder RF | title = Nelfinavir inhibits maturation and export of herpes simplex virus 1 | journal = Journal of Virology | volume = 88 | issue = 10 | pages = 5455–5461 | date = May 2014 | pmid = 24574416 | pmc = 4019105 | doi = 10.1128/JVI.03790-13 }}</ref> and the [[Kaposi's sarcoma virus]].<ref>{{cite journal | vauthors = Gantt S, Carlsson J, Ikoma M, Gachelet E, Gray M, Geballe AP, Corey L, Casper C, Lagunoff M, Vieira J | display-authors = 6 | title = The HIV protease inhibitor nelfinavir inhibits Kaposi's sarcoma-associated herpesvirus replication in vitro | journal = Antimicrobial Agents and Chemotherapy | volume = 55 | issue = 6 | pages = 2696–2703 | date = June 2011 | pmid = 21402841 | pmc = 3101462 | doi = 10.1128/AAC.01295-10 }}</ref>

===Anti-virulence activity===

Nelfinavir and simple derivatives have been found to inhibit the production of the [[virulence factor]] [[streptolysin|streptolysin S]], a [[cytolysin]] produced by the human [[pathogen]] ''[[Streptococcus pyogenes]]''.<ref name="pmid25668590">{{cite journal | vauthors = Maxson T, Deane CD, Molloy EM, Cox CL, Markley AL, Lee SW, Mitchell DA | title = HIV protease inhibitors block streptolysin S production | journal = ACS Chemical Biology | volume = 10 | issue = 5 | pages = 1217–1226 | date = May 2015 | pmid = 25668590 | pmc = 4574628 | doi = 10.1021/cb500843r }}</ref> 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]].<ref name="pmid25668590" />

== Interactions ==

{{unreferenced section|date=April 2022}}

Nelfinavir's interaction profile is similar to that of other [[antiretroviral drug|protease inhibitors]]. Most interactions occur at the level of the [[Cytochrome P450 oxidase|Cytochrome P450]] isozymes [[CYP3A4|3A4]] and [[CYP2C19]], by which nelfinavir is metabolised.

== Pharmacology ==

{{unreferenced section|date=April 2022}}

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 (pharmacology)|protease inhibitor]]: it inhibits [[HIV-1 protease|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<ref name=Shim2014>{{cite journal | vauthors = Shim JS, Liu JO | title = Recent advances in drug repositioning for the discovery of new anticancer drugs | journal = International Journal of Biological Sciences | volume = 10 | issue = 7 | pages = 654–663 | year = 2014 | pmid = 25013375 | pmc = 4081601 | doi = 10.7150/ijbs.9224 }}</ref> (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{{clarify|date=May 2012}} 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.<ref>{{cite journal | vauthors = Kaldor SW, Kalish VJ, Davies JF, Shetty BV, Fritz JE, Appelt K, Burgess JA, Campanale KM, Chirgadze NY, Clawson DK, Dressman BA, Hatch SD, Khalil DA, Kosa MB, Lubbehusen PP, Muesing MA, Patick AK, Reich SH, Su KS, Tatlock JH | display-authors = 6 | title = Viracept (nelfinavir mesylate, AG1343): a potent, orally bioavailable inhibitor of HIV-1 protease | journal = Journal of Medicinal Chemistry | volume = 40 | issue = 24 | pages = 3979–3985 | date = November 1997 | pmid = 9397180 | doi = 10.1021/jm9704098 }}</ref> 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]].{{cn|date=November 2022}}

The US [[Food and Drug Administration]] (FDA) approved it for therapeutic use in March 1997,{{Citation needed|date=April 2011}} making it the twelfth{{Citation needed|date=April 2011}} approved antiretroviral. The initial product launched proved to be the largest{{Citation needed|date=April 2011}} "biotech launch" in the history of the pharmaceutical industry, achieving first full year sales exceeding $US335M.{{Citation needed|date=April 2011}} Agouron's [[patent]] on the drug expired in 2014.

In June 2007, both the [[Medicines and Healthcare products Regulatory Agency]] and the [[European Medicines Agency]]<ref>[http://www.emea.europa.eu/pdfs/general/direct/pr/25128307en.pdf Press release] from the [[European Medicines Agency]] regarding possible genotoxic ethyl mesylate contamination</ref> 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.<ref>{{cite journal | vauthors = Chow WA, Jiang C, Guan M | title = Anti-HIV drugs for cancer therapeutics: back to the future? | journal = The Lancet. Oncology | volume = 10 | issue = 1 | pages = 61–71 | date = January 2009 | pmid = 19111246 | doi = 10.1016/S1470-2045(08)70334-6 }}</ref> 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]]).<ref name="pmid17785575">{{cite journal | vauthors = Gills JJ, Lopiccolo J, Tsurutani J, Shoemaker RH, Best CJ, Abu-Asab MS, Borojerdi J, Warfel NA, Gardner ER, Danish M, Hollander MC, Kawabata S, Tsokos M, Figg WD, Steeg PS, Dennis PA | display-authors = 6 | title = 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 | journal = Clinical Cancer Research | volume = 13 | issue = 17 | pages = 5183–5194 | date = September 2007 | pmid = 17785575 | doi = 10.1158/1078-0432.CCR-07-0161 | doi-access = free }}</ref> When Nelfinavir was given to laboratory mice with tumors of the prostate or of the brain, it could suppress tumor growth in these animals.<ref>{{cite journal | vauthors = Pyrko P, Kardosh A, Wang W, Xiong W, Schönthal AH, Chen TC | title = HIV-1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress | journal = Cancer Research | volume = 67 | issue = 22 | pages = 10920–10928 | date = November 2007 | pmid = 18006837 | doi = 10.1158/0008-5472.CAN-07-0796 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Yang Y, Ikezoe T, Takeuchi T, Adachi Y, Ohtsuki Y, Takeuchi S, Koeffler HP, Taguchi H | display-authors = 6 | title = 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 | journal = Cancer Science | volume = 96 | issue = 7 | pages = 425–433 | date = July 2005 | pmid = 16053514 | doi = 10.1111/j.1349-7006.2005.00063.x | s2cid = 44702882 | doi-access = | pmc = 11158579 }}</ref> 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]].<ref>{{cite journal | vauthors = Koltai T | title = Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity | journal = F1000Research | volume = 4 | issue = 2 | pages = 9 | date = 2015 | pmid = 26097685 | pmc = 4457118 | doi = 10.12688/f1000research.5827.2 | doi-access = free }}</ref>

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.<ref>{{cite web|url=https://clinicaltrials.gov/ct2/results?term=Nelfinavir+cancer|title=Search of: Nelfinavir cancer - List Results - ClinicalTrials.gov|website=clinicaltrials.gov}}</ref> 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]].{{cn|date=November 2022}}

{{as of |April 2022}}, nelfinavir is being studied as a [[radiosensitizer|radiosensitizing agent]] as part of treatment of advanced cervical cancer.<ref>{{ClinicalTrialsGov|NCT03256916|A Phase III Randomized Clinical Trial to Study the Radiosensitizing Effect of Nelfinavir in Locally Advanced Carcinoma of Uterine Cervix.}}</ref>

== References ==

{{reflist}}

== Further reading ==

{{refbegin}}

* {{cite journal | vauthors = Pai VB, Nahata MC | title = Nelfinavir mesylate: a protease inhibitor | journal = The Annals of Pharmacotherapy | volume = 33 | issue = 3 | pages = 325–339 | date = March 1999 | pmid = 10200859 | doi = 10.1345/aph.18089 | s2cid = 24066955 }}

* {{cite journal | vauthors = Bardsley-Elliot A, Plosker GL | title = Nelfinavir: an update on its use in HIV infection | journal = Drugs | volume = 59 | issue = 3 | pages = 581–620 | date = March 2000 | pmid = 10776836 | doi = 10.2165/00003495-200059030-00014 | doi-access = free }}

{{refend}}

{{Antiretroviral drug}}

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[[Category:Benzamides]]

[[Category:CYP3A4 inhibitors]]

[[Category:Decahydroisoquinolines]]

[[Category:Hepatotoxins]]

[[Category:HIV protease inhibitors]]

[[Category:Drugs developed by Hoffmann-La Roche]]

[[Category:Drugs developed by Pfizer]]

[[Category:Phenols]]

[[Category:Thioethers]]

[[Category:Tert-butyl compounds]]