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PF-07321332 Sale

(Synonyms: PF-07321332) 目录号 : GC62631

PF-07321332 (Nirmatrelvir)是一种口服的严重急性呼吸综合征冠状病毒2主蛋白酶(Mpro)抑制剂,在体外具有强效的泛人类冠状病毒活性。

PF-07321332 Chemical Structure

Cas No.:2628280-40-8

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥825.00
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5mg
¥750.00
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10mg
¥1,200.00
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50mg
¥3,250.00
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100mg
¥5,500.00
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Sample solution is provided at 25 µL, 10mM.

Description

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 <1 hour, respectively, after intravenous dosing [6].

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.

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.

化学性质

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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