Nirmatrelvir

Last updated

Nirmatrelvir
PF-07321332.svg
Clinical data
Pronunciation /nɜːrˈmætrəlvɪər/
nur-MAT-rəl-veer or /ˌnɜːrməˈtrɛlvɪər/
NUR-mə-TREL-veer
Other namesPF-07321332
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
  • None
Legal status
Legal status
Identifiers
  • (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
Formula C23H32F3N5O4
Molar mass 499.535 g·mol−1
3D model (JSmol)
Melting point 192.9 °C (379.2 °F) [3]
  • CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F)C(=O)N[C@@H](C[C@@H]3CCNC3=O)C#N)C
  • InChI=1S/C23H32F3N5O4/c1-21(2,3)16(30-20(35)23(24,25)26)19(34)31-10-13-14(22(13,4)5)15(31)18(33)29-12(9-27)8-11-6-7-28-17(11)32/h11-16H,6-8,10H2,1-5H3,(H,28,32)(H,29,33)(H,30,35)/t11-,12-,13-,14-,15-,16+/m0/s1
  • Key:LIENCHBZNNMNKG-OJFNHCPVSA-N
X-ray crystal structure (PDB:7SI9 and 7VH8) of the SARS-CoV-2 protease inhibitor nirmatrelvir bound to the viral 3CLpro protease enzyme. Ribbon diagram of the protein with the drug shown as sticks. The catalytic residues (His41, Cys145) are shown as yellow sticks. Xray crystal structure PDB-7si9.png
X-ray crystal structure (PDB:7SI9 and 7VH8) of the SARS-CoV-2 protease inhibitor nirmatrelvir bound to the viral 3CLpro protease enzyme. Ribbon diagram of the protein with the drug shown as sticks. The catalytic residues (His41, Cys145) are shown as yellow sticks.

Nirmatrelvir is an antiviral medication developed by Pfizer which acts as an orally active 3C-like protease inhibitor. [3] [4] [5] [6] [7] It is part of a nirmatrelvir/ritonavir combination used to treat COVID-19 and sold under the brand name Paxlovid. [8]

Contents

Development

Pharmaceutical

Coronaviral proteases cleave multiple sites in the viral polyprotein, usually after there are glutamine residues. Early work on related human rhinoviruses showed that the flexible glutamine side chain in inhibitors could be replaced by a rigid pyrrolidone. [9] [10] These drugs had been further developed prior to the COVID-19 pandemic for other diseases including SARS. [11] The utility of targeting the 3CL protease in a real world setting was first demonstrated in 2018 when GC376 (a prodrug of GC373) was used to treat the previously 100% lethal cat coronavirus disease, feline infectious peritonitis, caused by feline coronavirus. [12] Nirmatrelvir and GC373 are both peptidomimetics, share the aforementioned pyrrolidone in P1 position and are competitive inhibitors. They use a nitrile and an aldehyde respectively to bind the catalytic cysteine. [13] [14] Pfizer investigated two series of compounds, with nitrile and benzothiazol-2-yl ketone as the reactive group, respectively, and in the end settled on using nitrile. [15]

Nirmatrelvir was developed by modification of the earlier clinical candidate lufotrelvir, [16] [ full citation needed ] [17] [18] which is also a covalent protease inhibitor but its active element is a phosphate prodrug of a hydroxyketone. Lufotrelvir needs to be administered intravenously limiting its use to a hospital setting. Stepwise modification of the tripeptide peptidomimetic led to nirmatrelvir, which is suitable for oral administration. [3] Key changes include a reduction in the number of hydrogen bond donors, and the number of rotatable bonds by introducing a rigid bicyclic non-canonical amino acid (specifically, a "fused cyclopropyl ring with two methyl groups" [15] ), which mimics the leucine residue found in earlier inhibitors. This residue had previously been used in the synthesis of boceprevir. [19]

Tert-leucine (abbreviation: Tle) used in the P3 position of nirmatrelvir was identified first as optimal non-canonical amino acid in potential drug targeting SARS-CoV-2 3C-like protease using combinatorial chemistry (hybrid combinatorial substrate library technology). [20] [21] The leucine-like residue resulted in loss of a nearby contact with a glutamine on the 3C-like protease. [15] To compensate, Pfizer tried adding methane sulfonamide, acetamide and trifluoroacetamide, discovering that of the three, trifluoroacetamide resulted in superior oral bioavailability. [15]

Chemistry and pharmacology

Full details of the synthesis of nirmatrelvir were first published by scientists from Pfizer.

PF-07321332 synthesis.svg

In the penultimate step a synthetic homochiral amino acid is coupled with a homochiral amino amide using the water-soluble carbodiimide EDCI as a coupling agent. The resulting intermediate is then treated with Burgess reagent, which dehydrates the amide group to the nitrile of the product. [3]

Nirmatrelvir is a covalent inhibitor, binding directly to the catalytic cysteine (Cys145) residue of the cysteine protease enzyme. [22]

In the co-packaged medication nirmatrelvir/ritonavir, ritonavir serves to slow the metabolism of nirmatrelvir via cytochrome enzyme inhibition, thereby increasing the circulating concentration of the main drug. [23] This effect is also used in HIV therapy, where ritonavir is used in combination with another protease inhibitor to similarly enhance their pharmacokinetics. [24]

Society and culture

Licensing

In November 2021, Pfizer signed a license agreement with the United Nations–backed Medicines Patent Pool to allow nirmatrelvir to be manufactured and sold in 95 countries. [25] Pfizer stated that the agreement will allow local medicine manufacturers to produce the pill "with the goal of facilitating greater access to the global population". The deal excludes several countries with major COVID-19 outbreaks including Brazil, China, Russia, Argentina, and Thailand. [26] [27]

Names

Nirmatrelvir is the international nonproprietary name [28]

Research

The research that led to nirmatrelvir began in March 2020, when Pfizer formally launched a project at its Cambridge, Massachusetts site to develop antiviral drugs for treating COVID-19. [15] In July 2020, Pfizer chemists were able to synthesize nirmatrelvir for the first time. [15] In September 2020, Pfizer completed a pharmacokinetic study in rats which suggested that nirmatrelvir could be administered orally. [15] The actual synthesis of the drug for laboratory research and for clinical trials was carried out at Pfizer's Groton, Connecticut site. [29]

In February 2021, Pfizer launched the company's first phase I trial of PF-07321332 (nirmatrelvir) [30] at its clinical research unit in New Haven, Connecticut. [29]

A study published in March 2023 reported that treatment with nirmatrelvir within five days of initial infection reduced the risk of long COVID relative to patients who did not receive Paxlovid. [31]

A 2024 study found that "the time to sustained alleviation of all signs and symptoms of Covid-19 did not differ significantly between participants who received nirmatrelvir–ritonavir and those who received placebo." [32]

Related Research Articles

Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS, hepatitis C and COVID-19. These protease inhibitors prevent viral replication by selectively binding to viral proteases and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles.

<span class="mw-page-title-main">Ritonavir</span> Antiretroviral medication

Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor, though it now mainly serves to boost the potency of other protease inhibitors. It may also be used in combination with other medications to treat hepatitis C and COVID-19. It is taken by mouth.

<span class="mw-page-title-main">Lopinavir</span> Chemical compound

Lopinavir is an antiretroviral of the protease inhibitor class. It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir (lopinavir/ritonavir).

<span class="mw-page-title-main">Umifenovir</span> Chemical compound

Umifenovir, sold under the brand name Arbidol, is sold and used as an antiviral medication for influenza in Russia and China. The drug is manufactured by Pharmstandard. It is not approved by the U.S. Food and Drug Administration (FDA) for the treatment or prevention of influenza.

<span class="mw-page-title-main">Camostat</span> Serine protease inhibitor

Camostat is a serine protease inhibitor. Serine protease enzymes have a variety of functions in the body, and so camostat has a diverse range of uses. Camostat is approved in Japan for the treatment of chronic pancreatitis and postoperative reflux esophagitis. The oral proteolytic enzyme inhibitor has been on the market since 1985 under the trade name Foipan Tablets. The manufacturer is Ono Pharmaceutical. The drug is used in the treatment of some forms of cancer and is also effective against some viral infections, as well as inhibiting fibrosis in liver or kidney disease or pancreatitis.

<span class="mw-page-title-main">Lopinavir/ritonavir</span> Combination medication for HIV/AIDS

Lopinavir/ritonavir (LPV/r), sold under the brand name Kaletra among others, is a fixed-dose combination antiretroviral medication for the treatment and prevention of HIV/AIDS. It combines lopinavir with a low dose of ritonavir. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. It is taken by mouth as a tablet, capsule, or solution.

<span class="mw-page-title-main">3C-like protease</span> Class of enzymes

The 3C-like protease (3CLpro) or main protease (Mpro), formally known as C30 endopeptidase or 3-chymotrypsin-like protease, is the main protease found in coronaviruses. It cleaves the coronavirus polyprotein at eleven conserved sites. It is a cysteine protease and a member of the PA clan of proteases. It has a cysteine-histidine catalytic dyad at its active site and cleaves a Gln–(Ser/Ala/Gly) peptide bond.

<span class="mw-page-title-main">Rupintrivir</span> Chemical compound

Rupintrivir is a peptidomimetic antiviral drug which acts as a 3C and 3CL protease inhibitor. It was developed for the treatment of rhinoviruses, and has subsequently been investigated for the treatment of other viral diseases including those caused by picornaviruses, norovirus, and coronaviruses, such as SARS and COVID-19.

<span class="mw-page-title-main">COVID-19 drug repurposing research</span> Drug repurposing research related to COVID-19

Drug repositioning is the repurposing of an approved drug for the treatment of a different disease or medical condition than that for which it was originally developed. This is one line of scientific research which is being pursued to develop safe and effective COVID-19 treatments. Other research directions include the development of a COVID-19 vaccine and convalescent plasma transfusion.

<span class="mw-page-title-main">COVID-19 drug development</span> Preventative and therapeutic medications for COVID-19 infection

COVID-19 drug development is the research process to develop preventative therapeutic prescription drugs that would alleviate the severity of coronavirus disease 2019 (COVID-19). From early 2020 through 2021, several hundred drug companies, biotechnology firms, university research groups, and health organizations were developing therapeutic candidates for COVID-19 disease in various stages of preclinical or clinical research, with 419 potential COVID-19 drugs in clinical trials, as of April 2021.

<span class="mw-page-title-main">GC376</span> Broad-spectrum antiviral medication

GC376 is a broad-spectrum antiviral medication under development by the biopharmaceutical company Anivive Lifesciences for therapeutic uses in humans and animals. Anivive licensed the exclusive worldwide patent rights to GC376 from Kansas State University. As of 2020, GC376 is being investigated as a treatment for COVID-19. GC376 shows activity against many human and animal viruses, including coronavirus and norovirus; the most extensive research has been multiple in vivo studies in cats treating a coronavirus, which causes deadly feline infectious peritonitis. Other research supports use in porcine epidemic diarrhea virus.

<span class="mw-page-title-main">GS-441524</span> Metabolite of remdesivir

GS-441524 is a nucleoside analogue antiviral drug which was developed by Gilead Sciences. It is the main plasma metabolite of the antiviral prodrug remdesivir, and has a half-life of around 24 hours in human patients. Remdesivir and GS-441524 were both found to be effective in vitro against feline coronavirus strains responsible for feline infectious peritonitis (FIP), a lethal systemic disease affecting domestic cats. Remdesivir was never tested in cats, but GS-441524 has been found to be effective treatment for FIP.

The treatment and management of COVID-19 combines both supportive care, which includes treatment to relieve symptoms, fluid therapy, oxygen support as needed, and a growing list of approved medications. Highly effective vaccines have reduced mortality related to SARS-CoV-2; however, for those awaiting vaccination, as well as for the estimated millions of immunocompromised persons who are unlikely to respond robustly to vaccination, treatment remains important. Some people may experience persistent symptoms or disability after recovery from the infection, known as long COVID, but there is still limited information on the best management and rehabilitation for this condition.

<span class="mw-page-title-main">Lufotrelvir</span> Chemical compound

Lufotrelvir (PF-07304814) is an antiviral drug developed by Pfizer which acts as a 3CL protease inhibitor. It is a prodrug with the phosphate group being cleaved in vivo to yield the active agent PF-00835231. Lufotrelvir is in human clinical trials for the treatment of COVID-19, and shows good activity against COVID-19 including several variant strains, but unlike the related drug nirmatrelvir it is not orally active and must be administered by intravenous infusion, and so has been the less favoured candidate for clinical development overall.

<span class="mw-page-title-main">Nirmatrelvir/ritonavir</span> Antiviral combination medication

Nirmatrelvir/ritonavir, sold under the brand name Paxlovid, is a co-packaged medication used as a treatment for COVID‑19. It contains the antiviral medications nirmatrelvir and ritonavir and was developed by Pfizer. Nirmatrelvir inhibits SARS-CoV-2 main protease, while ritonavir is a strong CYP3A inhibitor, slowing down nirmatrelvir metabolism and therefore boosting its effect. It is taken by mouth.

<span class="mw-page-title-main">Ensitrelvir</span> COVID-19 SARS-CoV-2 3CL-protease-inhibitor antiviral drug

Ensitrelvir, sold under the brand name Xocova is an antiviral medication used as a treatment for COVID-19. It was developed by Shionogi in partnership with Hokkaido University and acts as an orally active 3C-like protease inhibitor. It is taken by mouth.

<span class="mw-page-title-main">Simnotrelvir/ritonavir</span> Antiviral combination medication

Simnotrelvir/ritonavir is a pharmaceutical drug used for the treatment of COVID-19. Simnotrelvir/ritonavir is a combination drug of simnotrelvir, an inhibitor of SARS-CoV-2 3CLpro, and ritonavir, a CYP3A inhibitor.

<span class="mw-page-title-main">Olgotrelvir</span> COVID-19 SARS-CoV-2 3CL-protease-inhibitor antiviral drug

Olgotrelvir (STI-1558) is an experimental antiviral medication being studied as a potential treatment for COVID-19. It is believed to work by inhibiting the SARS-CoV-2 main protease (Mpro), a key enzyme that SARS-CoV-2 needs to replicate, and by blocking viral entry.

<span class="mw-page-title-main">Jun12682</span> Antiviral drug

Jun12682 is an experimental antiviral medication being studied as a potential treatment for COVID-19. It is believed to work by inhibiting SARS-CoV-2 papain-like protease (PLpro), a crucial enzyme for viral replication.

<span class="mw-page-title-main">Ibuzatrelvir</span> Antiviral drug

Ibuzatrelvir is an experimental antiviral drug being developed by Pfizer for the treatment of COVID-19. It is a second-generation improvement over nirmatrelvir which has a similar chemical structure. One of the disadvantages of nirmatrelvir is that it has low metabolic stability and must be given in combination with ritonavir to limit its metabolic degradation in the body. Ibuzatrelvir incorporates modifications to the chemical structure of nirmatrelvir that give it enhanced oral bioavailability, so it does not require coadministration with ritonavir.

References

  1. ↑ "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 12 May 2022. Archived from the original on 3 April 2022. Retrieved 13 May 2022.
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  5. ↑ Ahmad B, Batool M, Ain QU, Kim MS, Choi S (August 2021). "Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations". International Journal of Molecular Sciences. 22 (17): 9124. doi: 10.3390/ijms22179124 . PMC   8430524 . PMID   34502033.
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  10. ↑ Dragovich PS, Prins TJ, Zhou R, Webber SE, Marakovits JT, Fuhrman SA, et al. (April 1999). "Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements". Journal of Medicinal Chemistry. 42 (7): 1213–1224. doi:10.1021/jm9805384. PMID   10197965.
  11. ↑ Pillaiyar T, Manickam M, Namasivayam V, Hayashi Y, Jung SH (July 2016). "An Overview of Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy". Journal of Medicinal Chemistry. 59 (14): 6595–6628. doi:10.1021/acs.jmedchem.5b01461. PMC   7075650 . PMID   26878082.
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  19. ↑ Njoroge FG, Chen KX, Shih NY, Piwinski JJ (January 2008). "Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection". Accounts of Chemical Research. 41 (1): 50–59. doi:10.1021/ar700109k. PMID   18193821. S2CID   2629035.
  20. ↑ Poreba M, Salvesen GS, Drag M (October 2017). "Synthesis of a HyCoSuL peptide substrate library to dissect protease substrate specificity". Nature Protocols. 12 (10): 2189–2214. doi:10.1038/nprot.2017.091. PMID   28933778. S2CID   23895951. Archived from the original on 27 December 2021. Retrieved 25 December 2021.
  21. ↑ Rut W, Groborz K, Zhang L, Sun X, Zmudzinski M, Pawlik B, et al. (October 2020). "SARS-CoV-2 M pro inhibitors and activity-based probes for patient-sample imaging". Nature Chemical Biology. 17 (2): 222–228. doi: 10.1038/s41589-020-00689-z . PMID   33093684. S2CID   224827220.
  22. ↑ Pavan M, Bolcato G, Bassani D, Sturlese M, Moro S (December 2021). "Supervised Molecular Dynamics (SuMD) Insights into the mechanism of action of SARS-CoV-2 main protease inhibitor PF-07321332". Journal of Enzyme Inhibition and Medicinal Chemistry. 36 (1): 1646–1650. doi:10.1080/14756366.2021.1954919. PMC   8300928 . PMID   34289752.
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  24. ↑ Hull MW, Montaner JS (April 2011). "Ritonavir-boosted protease inhibitors in HIV therapy". Annals of Medicine. 43 (5): 375–388. doi:10.3109/07853890.2011.572905. PMID   21501034. S2CID   21400449.
  25. ↑ "Pfizer and The Medicines Patent Pool (MPP) Sign Licensing Agreement for COVID-19 Oral Antiviral Treatment Candidate to Expand Access in Low- and Middle-Income Countries" (Press release). Pfizer. 16 November 2021. Archived from the original on 17 November 2021. Retrieved 17 November 2021– via Business Wire.
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  28. ↑ World Health Organization (2022). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 88". WHO Drug Information. 36 (3). hdl: 10665/363551 .
  29. 1 2 Green R (23 December 2021). "Pfizer scientists in Groton played a critical role in development of new COVID-19 pill". The Hartford Courant. Archived from the original on 15 January 2022. Retrieved 15 January 2022.
  30. ↑ Clinical trial number NCT04756531 for "Study Of PF-07321332 In Healthy Participants" at ClinicalTrials.gov
  31. ↑ Xie Y, Choi T, Al-Aly Z (March 2023). "Association of Treatment With Nirmatrelvir and the Risk of Post-COVID-19 Condition". JAMA Internal Medicine . 183 (6): 554–564. doi:10.1001/jamainternmed.2023.0743. PMC   10037200 . PMID   36951829.
  32. ↑ Hammond J, Fountaine RJ, Yunis C, Fleishaker D, Almas M, Bao W, et al. (April 2024). "Nirmatrelvir for Vaccinated or Unvaccinated Adult Outpatients with Covid-19". The New England Journal of Medicine. 390 (13): 1186–1195. doi:10.1056/NEJMoa2309003. PMC   11156287 . PMID   38598573.
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