Asunaprevir (BMS-650032)NS3 protease inhibitor CAS# 630420-16-5 |
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Quality Control & MSDS
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| Cas No. | 630420-16-5 | SDF | Download SDF |
| PubChem ID | 56843464 | Appearance | Powder |
| Formula | C35H46ClN5O9S | M.Wt | 748.29 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | BMS-650032 | ||
| Solubility | DMSO : ≥ 100 mg/mL (133.64 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | tert-butyl N-[(2S)-1-[(2S,4R)-4-(7-chloro-4-methoxyisoquinolin-1-yl)oxy-2-[[(1R)-1-(cyclopropylsulfonylcarbamoyl)-2-ethenylcyclopropyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate | ||
| SMILES | CC(C)(C)C(C(=O)N1CC(CC1C(=O)NC2(CC2C=C)C(=O)NS(=O)(=O)C3CC3)OC4=NC=C(C5=C4C=C(C=C5)Cl)OC)NC(=O)OC(C)(C)C | ||
| Standard InChIKey | XRWSZZJLZRKHHD-XVALYAAGSA-N | ||
| Standard InChI | InChI=1S/C35H46ClN5O9S/c1-9-19-16-35(19,31(44)40-51(46,47)22-11-12-22)39-28(42)25-15-21(49-29-24-14-20(36)10-13-23(24)26(48-8)17-37-29)18-41(25)30(43)27(33(2,3)4)38-32(45)50-34(5,6)7/h9-10,13-14,17,19,21-22,25,27H,1,11-12,15-16,18H2,2-8H3,(H,38,45)(H,39,42)(H,40,44)/t19?,21-,25+,27-,35-/m1/s1 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | Asunaprevir is a potent hepatitis C virus (HCV) NS3 protease inhibitor, with the IC50 of 0.2 nM-3.5 nM.In Vitro:In multiple experiments, populations of resistant colonies are markedly reduced when cells are treated with a combination of DCV and Asunaprevir[1]. Asunaprevir (ASV) inhibits the NS3 proteolytic activity of genotype 1a (H77 strain) and genotype 1b (J4L6S strain), with IC50s of 0.7 and 0.3 nM, respectively. The EC50s of ASV against replicons encoding the NS3 protease domains representing genotypes 1a, 1b, and 4a, range from 1.2 to 4.0 nM[2]. Replicon cells are maintained under selective pressure with asunaprevir at concentrations of 10 and 30 times the EC50 values (50 or 150 nM final concentrations, respectively). For genotype 1b resistance selection, replicon cells are maintained in the presence of asunaprevir at 10 or 30 times the EC50 values (30 or 90 nM final concentrations, respectively)[3]. Asunaprevir, administered at single or multiple doses of 200 to 600 mg twice daily, is generally well tolerated, achieving rapid and substantial decreases in HCV RNA levels in subjects chronically infected with genotype 1 HCV[4].In Vivo:Asunaprevir (ASV, 3-15 mg/kg, p.o.) displays a hepatotropic disposition (liver-to-plasma ratios ranging from 40- to 359-fold across species) in several animal species. Twenty-four hours postdose, liver exposures across all species tested are ≥110-fold above the inhibitor EC50 observed with HCV genotype-1 replicons[2]. References: | |||||
Asunaprevir (BMS-650032) Dilution Calculator
Asunaprevir (BMS-650032) Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.3364 mL | 6.6819 mL | 13.3638 mL | 26.7276 mL | 33.4095 mL |
| 5 mM | 0.2673 mL | 1.3364 mL | 2.6728 mL | 5.3455 mL | 6.6819 mL |
| 10 mM | 0.1336 mL | 0.6682 mL | 1.3364 mL | 2.6728 mL | 3.341 mL |
| 50 mM | 0.0267 mL | 0.1336 mL | 0.2673 mL | 0.5346 mL | 0.6682 mL |
| 100 mM | 0.0134 mL | 0.0668 mL | 0.1336 mL | 0.2673 mL | 0.3341 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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Asunaprevir is an orally efficacious inhibitor of NS3 protease with IC50 value of 1nM [1].
Asunaprevir is an inhibitor of hepatitis C virus (HCV) NS3 protease. It can inhibit 6 major genotypes of HCV NS3/4A protease with IC50 values of 0.7nM, 0.3nM, 15nM, 78nM, 320nM, 1.6nM, 1.7nM and 0.9nM, respectively for genotype 1a, 1b, 2a, 2b, 3a, 4a, 5a and 6a, respectively. When using the purified recombinant full-length HCV NS3/4A protease complexes, asunaprevir shows the Ki values of 0.4nM and 0.2nM, respectively for genotype 1a and genotype 1b. The mechanism of the inhibition is that the acylsulfonamide of asunaprevir interacts with the catalytic site of NS3 protease in a noncovalent manner. Asunaprevir inhibits HCV RNA replication in different cell lines, including liver, T lymphocytes, lung, cervix, and embryonic kidney. It shows no obvious activity against other RNA viruses. The permeability of asunaprevir is similar to the compound with good absorption in humans. The tests of metabolism rate show that asunaprevir exhibits low to intermediate metabolic clearance. Plasma and tissue exposures in vivo indicate that asunaprevir displays a hepatotropic disposition [2].
References:
[1] Scola PM, Sun LQ, Wang AX, Chen J, Sin N, Venables BL, Sit SY, Chen Y, Cocuzza A, Bilder DM, D'Andrea SV, Zheng B, Hewawasam P, Tu Y, Friborg J, Falk P, Hernandez D, Levine S, Chen C, Yu F, Sheaffer AK, Zhai G, Barry D, Knipe JO, Han YH, Schartman R, Donoso M, Mosure K, Sinz MW, Zvyaga T, Good AC, Rajamani R, Kish K, Tredup J, Klei HE, Gao Q, Mueller L, Colonno RJ, Grasela DM, Adams SP, Loy J, Levesque PC, Sun H, Shi H, Sun L, Warner W, Li D, Zhu J, Meanwell NA, McPhee F. The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection. J Med Chem. 2014 Mar 13;57(5):1730-52.
[2] McPhee F, Sheaffer AK, Friborg J, Hernandez D, Falk P, Zhai G, Levine S, Chaniewski S, Yu F, Barry D, Chen C, Lee MS, Mosure K, Sun LQ, Sinz M, Meanwell NA, Colonno RJ, Knipe J, Scola P. Preclinical Profile and Characterization of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir (BMS-650032). Antimicrob Agents Chemother. 2012 Oct;56(10):5387-96.
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The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection.[Pubmed:24564672]
J Med Chem. 2014 Mar 13;57(5):1730-52.
The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).
Preclinical Pharmacokinetics and In Vitro Metabolism of Asunaprevir (BMS-650032), a Potent Hepatitis C Virus NS3 Protease Inhibitor.[Pubmed:25631585]
J Pharm Sci. 2015 Sep;104(9):2813-23.
Asunaprevir (ASV; BMS-650032), a low nanomolar inhibitor of the hepatitis C virus (HCV) NS3 protease, is currently under development, in combination with other direct-acting antiviral (DAA) agents for the treatment of chronic HCV infection. Extensive nonclinical and pharmacokinetic studies have been conducted to characterize the ADME properties of ASV. ASV has a moderate to high clearance in preclinical species. In vitro reaction phenotyping studies demonstrated that the oxidative metabolism of ASV is primarily mediated via CYP3A4; however, studies in bile-duct cannulated rats and dogs suggest that biliary elimination may contribute to overall ASV clearance. ASV is shown to have hepatotropic disposition in all preclinical species tested (liver to plasma ratios >40). The translation of in vitro replicon potency to clinical viral load decline for a previous lead BMS-605339 was leveraged to predict a human dose of 2 mg BID for ASV. Clinical drug-drug interaction (DDI) studies have shown that at therapeutically relevant concentrations of ASV the potential for a DDI is minimal. The need for an interferon free treatment combined with ASV's initial clinical trial data support development of ASV as part of a fixed dose combination for the treatment of patients chronically infected with HCV genotype 1.
Asunaprevir (BMS-650032) for the treatment of hepatitis C virus.[Pubmed:26414905]
Expert Rev Anti Infect Ther. 2015;13(11):1307-17.
Asunaprevir, a second-generation NS3 protease inhibitor of hepatitis C virus (HCV), exhibits strong antiviral activity against HCV genotypes 1 and 4, but relatively weak activity against genotypes 2 and 3. For chronic HCV infection, asunaprevir with daclatasvir as an interferon-free dual treatment achieves a sustained virologic response of nearly 90% in genotype 1b, and a triple regimen with beclabuvir achieves an sustained virologic response >90%. Asunaprevir and daclatasvir dual treatment can be safely and effectively administered to liver transplant recipients with recurrent HCV. The major drawback of asunaprevir is its low threshold to resistance, which can be overcome by combining it with other direct-acting antivirals. Further studies of asunaprevir in combination with other direct-acting antivirals for the treatment of patients with HCV genotypes 1 or 4 and renal impairment or end-stage renal disease under hemodialysis, HIV-coinfection and liver and/or kidney transplant recipients are warranted.
Characterization of ADME properties of [(14)C]asunaprevir (BMS-650032) in humans.[Pubmed:26153443]
Xenobiotica. 2016;46(1):52-64.
1. Asunaprevir (ASV, BMS-650032), a highly selective and potent NS3 protease inhibitor, is currently under development for the treatment of chronic hepatic C virus infection. This study describes in vivo biotransformation in humans and the identification of metabolic enzymes of ASV. 2. Following a single oral dose of [(14)C]ASV to humans, the majority of radioactivity (>73% of the dose) was excreted in feces with <1% of the dose recovered in urine. Drug-related radioactivity readily appeared in circulation and the plasma radioactivity was mainly attributed to ASV. A few minor metabolites were observed in human plasma and are not expected to contribute to the pharmacological activity because of low levels. The area under the curve (AUC) values of each circulating metabolite in humans were well below their levels in animals used in the long-term toxicological studies. In bile and feces, intact ASV was a prominent radioactive peak suggesting that both metabolism and direct excretion played important roles in ASV clearance. 3. The primary metabolic pathways of ASV were hydroxylation, sulfonamide hydrolysis and the loss of isoquinoline. In vitro studies with human cDNA expressed CYP enzymes and with human liver microsomes (HLM) in the presence of selective chemical inhibitors demonstrated that ASV was primarily catalyzed by CYP3A4 and CYP3A5.
