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PF-07321332 Sale

(Synonyms: PF-07321332) 目录号 : GC62631

PF-07321332 (Nirmatrelvir) is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (Mpro) inhibitor with potent pan-human-coronavirus activity in vitro.

PF-07321332 Chemical Structure

Cas No.:2628280-40-8

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10mM (in 1mL DMSO)
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5mg
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10mg
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50mg
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100mg
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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Cell experiment [1]:

Cell lines

differentiated normal human bronchial epithelial (dNHBE) cells

Preparation Method

The dNHBE cells were grown on trans-well inserts consisting of approximately 1.2 × 106 cells in MatTek's proprietary culture medium added to the basolateral side, with the apical side exposed to a humidified 5% CO2 environment at 37 °C. On day 1, dNHBE cells were infected with SARS-CoV-2 strain USA-WA1/2020 at a MOI of approximately 0.0015 50% of the cell culture infectious dose (CCID50) per cell, and PF-07321332 treatment was carried out by inclusion of drug dilutions in basolateral culture media. At day 3 and day 5, virus released into the apical compartment was harvested by the addition of 0.4 ml culture media. The virus titer was then quantified by infecting Vero76 cells in a standard endpoint dilution assay and virus dose that was able to infect 50% of the cell cultures (CCID50 per ml) was calculated.

Reaction Conditions

0.1-10000 nM for 3 days

Applications

Treatment of dNHBE cells with varying concentrations of PF-07321332 for 3 days led to inhibition of SARS-CoV-2 viral replication, with EC50 and EC90 values of 61.8 and 181 nM, respectively.

Animal experiment [2]:

Animal models

8-week old female Charles River mice

Preparation Method

Pharmacokinetics studies were performed in an animal biosafety level 2 (ABSL2) facility. A total of 24 BALB/c mice were divided into 4 groups: group 1: untreated, infected control; group 2: 300 mg/kg PF-07321332; group 3: 1000 mg/kg PF-07321332, and group 4: untreated, uninfected control (for pharmacokinetic analysis and normal weight). Mice were anesthetized by intraperitoneal (i.p.) injection of ketamine/xylazine (50 mg/kg/5 mg/kg) and inoculated intranasally (i.n.) with 1 x 105 50% CCID50 of SARS-CoV-2 MA10 (90 ml/nares).

Dosage form

300,1000 mg/kg, i.p. ; 300,1000 mg/kg, BID, po.

Applications

PF-07321332 limits cellular infiltration and protects lung tissue from damage caused by virus replication.

References:

[1]: Owen D R, Allerton C M N, Anderson A S, et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19[J]. Science, 2021, 374(6575): 1586-1593.

产品描述

PF-07321332 (Nirmatrelvir) is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (Mpro) inhibitor with potent pan-human-coronavirus activity in vitro [1]. PF-07321332 inhibited activity against SARS-CoV-2 Mpro with the IC50 value of 0.023 µM [2].

PF-07321332 demonstrated potent inhibition in FRET Mpro assays representing Mpro from all coronavirus types known to infect humans [3,4,5], including beta-coronaviruses (SARS-CoV-2, SARS-CoV-1, HKU1, OC43, and MERS-CoV) as well as alpha-coronaviruses (229E and NL63) [6]. At the concentration tested (100 µM) of PF-07321332, no inhibitory effects were noted against several mammalian cysteine (caspase 2, cathepsin B, and cathepsin L), serine (chymotrypsin, elastase, and thrombin) and aspartyl (cathepsin D) proteases [6]. Treatment of dNHBE cells with varying concentrations of PF-07321332 for 3 days led to inhibition of SARS-CoV-2 viral replication, with EC50 and EC90 values of 61.8 and 181 nM, respectively [6].

After infection with SARS-CoV-2 MA10, mice treated twice daily with PF-07321332 (at both 300 and 1000 mg/kg doses) were protected from weight loss compared with vehicle-treated mice. At 4 days after infection, mice were sacrificed and lung viral titers were evaluated in CCID50 assays. Infected animals in the placebo group had robust infection in the lungs, whereas virus levels in mice treated with PF-07321332 were significantly reduced (300 and 1000 mg/kg PF-07321332-treated groups, respectively) [6]. PF-07321332 exhibited moderate plasma clearance (CLp) in rats and monkeys, with elimination half-lives (t1/2) of 5 hours and

References:
[1]. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19[J]. New England Journal of Medicine, 2022, 386(15): 1397-1408.
[2]. Li J, Lin C, Zhou X, et al. Structural Basis of the Main Proteases of Coronavirus Bound to Drug Candidate PF-07321332[J]. Journal of Virology, 2022, 96(8): e02013-21.
[3]. Wu F, Zhao S, Yu B, et al. A new coronavirus associated with human respiratory disease in China[J]. Nature, 2020, 579(7798): 265-269.
[4]. Zhou P, Yang X L, Wang X G, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin[J]. nature, 2020, 579(7798): 270-273.
[5]. Cui J, Li F, Shi Z L. Origin and evolution of pathogenic coronaviruses[J]. Nature reviews microbiology, 2019, 17(3): 181-192.
[6]. Owen D R, Allerton C M N, Anderson A S, et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19[J]. Science, 2021, 374(6575): 1586-1593.

Chemical Properties

Cas No. 2628280-40-8 SDF
别名 PF-07321332
分子式 C23H32F3N5O4 分子量 499.53
溶解度 DMSO : 140 mg/mL (280.26 mM; Need ultrasonic) 储存条件 Store at -20°C
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1 mM 2.0019 mL 10.0094 mL 20.0188 mL
5 mM 0.4004 mL 2.0019 mL 4.0038 mL
10 mM 0.2002 mL 1.0009 mL 2.0019 mL
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Research Update

An update on drugs with therapeutic potential for SARS-CoV-2 (COVID-19) treatment

Drug Resist Updat 2021 Dec;59:100794.PMID:34991982DOI:10.1016/j.drup.2021.100794.

The COVID-19 pandemic is one of the greatest threats to human health in the 21st century with more than 257 million cases and over 5.17 million deaths reported worldwide (as of November 23, 2021. Various agents were initially proclaimed to be effective against SARS-CoV-2, the etiological agent of COVID-19. Hydroxychloroquine, lopinavir/ritonavir, and ribavirin are all examples of therapeutic agents, whose efficacy against COVID-19 was later disproved. Meanwhile, concentrated efforts of researchers and clinicians worldwide have led to the identification of novel therapeutic options to control the disease including PAXLOVID™ (PF-07321332). Although COVID-19 cases are currently treated using a comprehensive approach of anticoagulants, oxygen, and antibiotics, the novel Pfizer agent PAXLOVID™ (PF-07321332), an investigational COVID-19 oral antiviral candidate, significantly reduced hospitalization time and death rates, based on an interim analysis of the phase 2/3 EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) randomized, double-blind study of non-hospitalized adult patients with COVID-19, who are at high risk of progressing to severe illness. The scheduled interim analysis demonstrated an 89 % reduction in risk of COVID-19-related hospitalization or death from any cause compared to placebo in patients treated within three days of symptom onset (primary endpoint). However, there still exists a great need for the development of additional treatments, as the recommended therapeutic options are insufficient in many cases. Thus far, mRNA and vector vaccines appear to be the most effective modalities to control the pandemic. In the current review, we provide an update on the progress that has been made since April 2020 in clinical trials concerning the effectiveness of therapies available to combat COVID-19. We focus on currently recommended therapeutic agents, including steroids, various monoclonal antibodies, remdesivir, baricitinib, anticoagulants and PAXLOVID™ summarizing the latest original studies and meta-analyses. Moreover, we aim to discuss other currently and previously studied agents targeting COVID-19 that either show no or only limited therapeutic activity. The results of recent studies report that hydroxychloroquine and convalescent plasma demonstrate no efficacy against SARS-CoV-2 infection. Lastly, we summarize the studies on various drugs with incoherent or insufficient data concerning their effectiveness, such as amantadine, ivermectin, or niclosamide.

An update of anti-viral treatment of COVID-19

Turk J Med Sci 2021 Dec 17;51(SI-1):3372-3390.PMID:34391321DOI:10.3906/sag-2106-250.

Background/aim: Currently there is not an effective antiviral treatment for COVID-19, but a large number of drugs have been evaluated since the beginning of the pandemic, and many of them have been used for the treatment of COVID-19 despite the preliminary or conflicting results of the clinical trials. We aimed to review and summarize all of the current knowledge on the antivirals for COVID-19 Results: There are 2 main drug groups for SARS-CoV-2: agents that target proteins or RNA of the virus or interfere with proteins or biological processes in the host that support the virus. The main drug groups include inhibitors of viral entry into the human cell (convalescent plasma, monoclonal antibodies, nanobodies, mini proteins, human soluble ACE-2, camostat, dutasteride, proxalutamide, bromhexin, hydroxychloroquine, umifenovir nitazoxanid, niclosamide, lactoferrin), inhibitors of viral proteases (lopinavir/ritonavir, PF-07321332, PF-07304814, GC376), inhibitors of viral RNA (remdesivir, favipiravir, molnupiravir, AT-527, merimepodib, PTC299), inhibitors of host proteins supporting virus (plitidepsin, fluvoxamine, ivermectin), and agents supporting host natural immunity (Interferons). Conclusion: When taking into account the results of all the available laboratory and clinical trials on the subject, monoclonal antibodies seem to be the most effective treatment for COVID-19 at the moment, and high-titer convalescent plasma also could be effective when administered during the early phase of the disease. As lopinavir/ritonavir, hydroxychloroquine, merimepodib, and umifenovir were found to be ineffective in RCTs, they should not be used. Additional studies are needed to define the role of remdesivir, favipiravir, interferons, ivermectin, dutasteride, proxulutamide, fluvoxamine, bromhexine, nitazoxanide, and niclosamid in the treatment of COVID-19. Finally, the results of phase trials are waited to learn whether or not the newer agents such as molnupiravir, PF-07321332, PF-07304814, plitidepsin and AT-527 are effective in the treatment of COVID-19.

Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations

Int J Mol Sci 2021 Aug 24;22(17):9124.PMID:34502033DOI:10.3390/ijms22179124.

The novel coronavirus disease, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), rapidly spreading around the world, poses a major threat to the global public health. Herein, we demonstrated the binding mechanism of PF-07321332, α-ketoamide, lopinavir, and ritonavir to the coronavirus 3-chymotrypsin-like-protease (3CLpro) by means of docking and molecular dynamic (MD) simulations. The analysis of MD trajectories of 3CLpro with PF-07321332, α-ketoamide, lopinavir, and ritonavir revealed that 3CLpro-PF-07321332 and 3CLpro-α-ketoamide complexes remained stable compared with 3CLpro-ritonavir and 3CLpro-lopinavir. Investigating the dynamic behavior of ligand-protein interaction, ligands PF-07321332 and α-ketoamide showed stronger bonding via making interactions with catalytic dyad residues His41-Cys145 of 3CLpro. Lopinavir and ritonavir were unable to disrupt the catalytic dyad, as illustrated by increased bond length during the MD simulation. To decipher the ligand binding mode and affinity, ligand interactions with SARS-CoV-2 proteases and binding energy were calculated. The binding energy of the bespoke antiviral PF-07321332 clinical candidate was two times higher than that of α-ketoamide and three times than that of lopinavir and ritonavir. Our study elucidated in detail the binding mechanism of the potent PF-07321332 to 3CLpro along with the low potency of lopinavir and ritonavir due to weak binding affinity demonstrated by the binding energy data. This study will be helpful for the development and optimization of more specific compounds to combat coronavirus disease.

Reproductive and developmental safety of nirmatrelvir (PF-07321332), an oral SARS-CoV-2 Mpro inhibitor in animal models

Reprod Toxicol 2022 Mar;108:56-61.PMID:35101563DOI:10.1016/j.reprotox.2022.01.006.

Nirmatrelvir (PF-07321332; NMV) the antiviral component of PAXLOVID™ is a potent and selective inhibitor of the SARS-CoV-2 main protease (Mpro), which plays a critical role in viral replication. PAXLOVID, comprised of nirmatrelvir and ritonavir (used as a pharmacokinetic enhancer), is an oral therapy currently in development as a therapeutic option for those infected with SARS-CoV-2 to prevent progression to severe disease, hospitalization, and death. PAXLOVID has been shown to be efficacious against hospitalization and death in two Phase 2/3 clinical studies that evaluated non hospitalized patients both with and without high risk factors for progression to severe illness. Given that males and females of reproductive age are included in the intended patient population, we assessed the potential effects of NMV up to the limit dose of 1000 mg/kg/day in ICH guideline embryo-fetal development studies in rats and rabbits, and a fertility and early embryonic development study in rats. There were no effects on male and female fertility or early embryonic development in rats, and no severe manifestations of developmental toxicity in rats or rabbits. The lack of adverse findings reported here in nonclinical species is consistent with the intended therapeutic target of NMV (a virus specific protein not present in mammalian cells), the favorable off-target selectivity profile, and lack of genetic toxicity. The results of these nonclinical studies with NMV along with existing ritonavir safety information indicate that there are no clinically relevant risks associated with PAXLOVID administration during pregnancy and in males and females of reproductive age.

An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19

Science 2021 Dec 24;374(6575):1586-1593.PMID:34726479DOI:10.1126/science.abl4784.

The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.