HCV 1a (EC50 = 1 nM); HCV 1b (EC50 = 0.21 nM); SARS-CoV 3CLpro (IC50 = 1.31 μM)

Paritaprevir exhibits antiviral activity in vitro against HCV GT1-4 and GT6 (EC50 range: 0.09 to 19 nM), while its EC50 against GT4a is 0.09 nM[2].

HCV genotype 1 infections can be treated with Paritaprevir, Ritonavir, Ombitasvir (an NS5A protein inhibitor), and Dasabuvir (an NS5B non-nucleoside polymerase inhibitor) with or without RBV[1][4]. Paritaprevir's acute toxicity is regarded as being minimal. Oral dosages of up to 600 mg/kg in rats and up to 100 mg/kg in dogs administered once showed no mortality and good tolerance. The exposures are low, particularly in male rats (rat 600 mg/kg, males: Cmax 1.82 μg/mL, AUC0-24 8.89 μg·h/mL; dog 100 mg/kg, mean: Cmax 61.3 μg/mL, AUC0-24 285 μg ·h/mL), though, because paritaprevir is administered without ritonavir as a PK enhancer.

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Paritaprevir achieves maximum concentrations after oral administration in a mean of 4-5 hours, with exposure increases exceeding dose proportionality. Approximately 50% of the total bioavailability occurs when food is administered. It exhibits high plasma protein binding (between 97-99.9%) and 16.7 liters of apparent volume of distribution. Paritaprevir is metabolized primarily by CYP3A4 and CYP3A5[1].

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Phenotypic evaluation of in vivo resistance development. [2]
Phenotypic analyses of viral isolates from baseline (before the first dose was administered) and at the end of 3 days of ABT-450/r monotherapy were performed in order to characterize the selection of resistant variants. The development of phenotypic resistance to ABT-450 during 3 days of dosing was assessed by calculating the fold change in EC50 at the end of the 3-day monotherapy compared to baseline (Table 4). Thirteen of the 24 patients (12 of 19 infected with genotype 1a and 1 of 5 infected with genotype 1b) had a viral load level sufficient (≥500 IU/ml) to allow amplification of the target gene at the end of the 3-day dosing period (5, 3, and 5 patients in the ABT-450/r 200/100-, 100/100-, and 50/100-mg treatment groups, respectively). [2]

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Administration of 30 mg/kg paritaprevir for 3 days protected rats from LPS-induced ALI, as reflected by the changes in the lung coefficient (from 0.75 to 0.64) and lung pathology scores (from 5.17 to 5.20). Furthermore, the levels of the protective adhesion protein VE-cadherin and tight junction protein claudin-5 increased, and the cytoplasmic p-FOX-O1 and nuclear β-catenin and FOX-O1 levels decreased[3].

Paritaprevir exhibits antiviral activity in vitro against HCV GT1-4 and GT6 (EC50 range: 0.09 to 19 nM), while its EC50 against GT4a is 0.09 nM.

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Antiviral activity against a panel of resistant mutants. [2]
The 1a-H77 and 1b-Con1 subgenomic replicon shuttle vector constructs used for introduction of mutations of interest in the NS3 gene were similar to the replicon cell line constructs described above, but in both cases the Neo gene was not present, and the HCV NS2 gene was inserted between the EMCV IRES and the NS3 gene (Fig. 2B). In addition, the 1a-H77 replicon construct had the adaptive mutation in NS3 protease encoding E1202G replaced with one encoding P1496L in NS3 helicase. An AscI restriction site was introduced into the NS2 gene 62 nucleotides upstream of the 5′ end of the NS3 gene, and a BstBI restriction site was introduced within the helicase domain of NS3 after the NS3 amino acid 251 codon. The introduction of these restriction sites did not result in an amino acid insertion or change in either the genotype 1a or 1b replicon. Mutations encoding resistance-associated variants were introduced by site-directed mutagenesis and confirmed by sequence analysis. Subgenomic replicon RNA was generated by linearization of plasmid DNA followed by in vitro transcription. Replicon RNA was transfected into Huh7-derived cells, and inhibition of replication of the HCV replicon by ABT-450 was measured using the luciferase assay as described above, except that cells were incubated for 4 days rather than 3 days prior to lysis. Replication efficiency was calculated as a percentage of wild-type replication using the following equation: 100 ×[(mutant 4-day luciferase activity/wild-type 4-day luciferase activity)/(mutant 4-h luciferase activity/wild-type 4-h luciferase activity)][2].

Antiviral activity in cell culture.[2]
Replicon cell lines were maintained in Dulbecco's modified Eagle medium (DMEM) supplemented with 100 IU/ml penicillin, 100 μg/ml streptomycin, and 200 μg/ml G418, all of which were from Invitrogen, as well as 10% (vol/vol) fetal bovine serum (FBS). The inhibitory effect of ABT-450 was evaluated by incubating replicon-containing cells in the presence of a series of ABT-450 dilutions for 3 days in the same medium containing 5% FBS, followed by measurement of firefly luciferase activity using the luciferase assay system. In assays measuring inhibitory activity in the presence of human plasma, the medium contained 40% human plasma and 5% FBS. The percent inhibition of HCV RNA replication was calculated for each compound concentration, and the 50% effective concentration (EC50) was calculated using nonlinear regression sigmoidal dose-response variable slope curve fitting to the 4-parameter logistic equation and GraphPad Prism 4 software. The cytotoxicity of ABT-450 was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay. The 50% cytotoxicity concentration (CC50) was calculated using nonlinear regression sigmoidal dose-response variable slope curve fitting as described above.

In this study, 75 patients meeting all eligibility criteria and none of the exclusion criteria were randomized to receive various doses of ABT-450/r, dasabuvir, or ABT-072. Only data from the 24 patients treated with ABT-450/r are discussed in this report. Eligibility criteria for study M11-602 included the following: age of 18 to 65 years, body mass index (BMI) of ≥18 and <35 kg/m2, chronic HCV genotype 1 infection for at least 6 months prior to study enrollment, plasma HCV RNA level of ≥100,000 IU/ml at screening, liver biopsy within the past 3 years with histology consistent with HCV-induced liver damage, and no evidence of cirrhosis. Exclusion criteria included the following: liver biopsy with a METAVIR fibrosis score of 3 or 4, positive test result for hepatitis B surface antigen or anti-HIV antibodies, history of major depression within the 2 years prior to enrollment, history of disease precluding the use of pegIFN or RBV, and unresolved clinically significant diseases other than HCV.[2]

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Patients were randomized to receive 1 of 3 doses of ABT-450/r (50/100 mg, 100/100 mg, or 200/100 mg) or placebo once daily (QD). Following 3 days of monotherapy, pegIFN alfa-2a at 180 μg/week and weight-based RBV at 1,000 to 1,200 mg/day were added, and the same dose of ABT-450/r or placebo was continued to complete a total of 12 weeks. At week 12, ABT-450/r or placebo was discontinued, and patients received pegIFN/RBV alone for up to 36 additional weeks.[2]

[1]. Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir: A Review in Chronic HCV Genotype 1 Infection. Drugs. 2015 Jun;75(9):1027-38. [2]. In vitro and in vivo antiviral activity and resistance profile of the hepatitis C virus NS3/4A protease inhibitor ABT-450. Antimicrob Agents Chemother. 2015 Feb;59(2):988-97. [3]. Paritaprevir ameliorates experimental acute lung injury in vitro and in vivo. Arch Pharm Res. 2023 Jun;46(6):564-572. [4]. Profile of paritaprevir/ritonavir/ombitasvir plus dasabuvir in the treatment of chronic hepatitis C virus genotype 1 infection. Drug Des Devel Ther. 2015 Nov 13;9:6083-94.
[5]. Hepatitis C Virus Genotype 4 Resistance and Subtype Demographic Characterization of Patients Treated with Ombitasvir plus Paritaprevir/ritonavir. Antimicrob Agents Chemother. 2015 Aug 17. pii: AAC.01229-15.
[6]. Bardoxolone and bardoxolone methyl, two Nrf2 activators in clinical trials, inhibit SARS-CoV-2 replication and its 3C-like protease. Signal Transduct Target Ther. 2021 May 29;6(1):212.
[7]. Drug-drug interaction profile of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol. 2015 Jul;63(1):20-9.

C40H47N7O9S

801.907688379288

801.315

1456607-71-8

Paritaprevir;1216941-48-8

90479564

Typically exists as solids at room temperature

5

12

7

57

1600

5

S(C1CC1)(NC(C12CC1C=CCCCCCC(C(N1CC(CC1C(N2)=O)OC1C2C=CC=CC=2C2C=CC=CC=2N=1)=O)NC(C1C=NC(C)=CN=1)=O)=O)(=O)=O.O.O

AWGQIDLXYMGEEH-RHSIAEQTSA-N

InChI=1S/C40H43N7O7S.2H2O/c1-24-21-42-33(22-41-24)35(48)43-32-16-6-4-2-3-5-11-25-20-40(25,39(51)46-55(52,53)27-17-18-27)45-36(49)34-19-26(23-47(34)38(32)50)54-37-30-14-8-7-12-28(30)29-13-9-10-15-31(29)44-37;;/h5,7-15,21-22,25-27,32,34H,2-4,6,16-20,23H2,1H3,(H,43,48)(H,45,49)(H,46,51);2*1H2/b11-5-;;/t25-,26-,32+,34+,40-;;/m1../s1

(1S,4R,6S,7Z,14S,18R)-N-cyclopropylsulfonyl-14-[(5-methylpyrazine-2-carbonyl)amino]-2,15-dioxo-18-phenanthridin-6-yloxy-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxamide;dihydrate

Paritaprevir dihydrate; 1456607-71-8; ABT-450 dihydrate; ABT 450 dihydrate; UNII-HRQ5901O78; HRQ5901O78; Paritaprevir (dihydrate); (1S,4R,6S,7Z,14S,18R)-N-cyclopropylsulfonyl-14-[(5-methylpyrazine-2-carbonyl)amino]-2,15-dioxo-18-phenanthridin-6-yloxy-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxamide;dihydrate; .

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)