ABT-072
目录号 : GC33977
ABT-072是非核苷NS5Bpolymerase的抑制剂，为治疗HCV的有效候选药。
Cas No.:1132936-00-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | To determine compound efficacy, HCV replicon cells are plated at a density of 104 per well in 96-well plates in DMEM media containing 10% FBS. Following incubation overnight, compounds serially diluted in DMSO, or DMSO alone, are added to individual wells to a final DMSO concentration of 0.5%. Cell plates are then incubated at 37°C. for 3 days prior to assaying for cytotoxicity and HCV inhibition. Cell viability is measured using an Alamar Blue assay and CC50 values are calculated using the median effect equation. |
References: [1]. Min Gao, et al. Combinations of Hepatitis C Virus Inhibitors. US 20120196794 A1 | |
ABT-072 is a nonnucleoside NS5B polymerase inhibitor and a candidate drug evaluated for treatment of hepatitis C virus.
ABT-072 inhibits non-nucleoside NS5B polymerase, and yields antiviral effects[1].
[1]. Min Gao, et al. Combinations of Hepatitis C Virus Inhibitors. US 20120196794 A1
| Cas No. | 1132936-00-5 | SDF | |
| Canonical SMILES | CS(=O)(NC1=CC=C(/C=C/C2=CC(N(C(N3)=O)C=CC3=O)=CC(C(C)(C)C)=C2OC)C=C1)=O | ||
| 分子式 | C24H27N3O5S | 分子量 | 469.55 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1297 mL | 10.6485 mL | 21.297 mL |
| 5 mM | 0.4259 mL | 2.1297 mL | 4.2594 mL |
| 10 mM | 0.213 mL | 1.0648 mL | 2.1297 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
A phase 2a trial of 12-week interferon-free therapy with two direct-acting antivirals (ABT-450/r, ABT-072) and ribavirin in IL28B C/C patients with chronic hepatitis C genotype 1
J Hepatol 2013 Jul;59(1):18-23.PMID:23439262DOI:10.1016/j.jhep.2013.02.009.
Background & aims: ABT-450 (combined with low-dose ritonavir, ABT-450/r) is a potent HCV NS3 protease inhibitor, and ABT-072 is a non-nucleoside NS5B polymerase inhibitor. The goal of this study was to evaluate the safety, tolerability, and efficacy of the peginterferon-free combination of ABT-450/r and ABT-072 with ribavirin in treatment-naïve patients with IL28B CC genotype, infected with HCV genotype 1. Methods: This was a phase 2a, multicenter, open-label, single-arm study in 11 treatment-naïve, non-cirrhotic HCV GT1-infected patients with IL28B rs12979860 genotype CC. Patients received ABT-450/r 150/100 mg once daily and ABT-072 400 mg once daily with weight-based ribavirin 1000-1200 mg/day dosed twice daily for 12 weeks. Results: Eight (73%) patients were male, 9 (82%) were Caucasian (including 3 who self-identified as Hispanic); mean baseline HCV RNA was 6.9 log₁₀ IU/ml (range 6.5-7.3 log₁₀ IU/ml). All 11 patients completed 12 weeks of treatment and maintained HCV RNA <25 IU/ml from weeks 4 through 12 of treatment. Ten patients (91%) achieved sustained virologic response 24 weeks post-treatment, with a second patient relapsing 36 weeks post-treatment. There were no deaths, serious or severe adverse events, or premature discontinuations. Adverse events were mostly mild and the most frequent were headache, fatigue, nausea, and dry skin. Conclusions: A 12-week regimen of ABT-450/r and ABT-072 with ribavirin was well tolerated with 9/11 patients achieving sustained virologic response through 36 weeks of post-treatment observation. These findings suggest that peginterferon-free regimens may have the potential to cure a high proportion of HCV genotype 1-infected patients.
Assessing Supersaturation and Its Impact on In Vivo Bioavailability of a Low-Solubility Compound ABT-072 With a Dual pH, Two-Phase Dissolution Method
J Pharm Sci 2016 Sep;105(9):2886-2895.PMID:27321234DOI:10.1016/j.xphs.2016.04.036.
ABT-072 is a candidate drug evaluated for treatment of hepatitis C virus. It is an acidic compound with extremely low intrinsic aqueous solubility. An in vitro dissolution-partition system, referred as biphasic test method, was used to characterize ABT-072 prototype formulations. This test used 2 aqueous dissolution media of pH 2 and 6.5 in a sequential manner to simulate the transition of drug in gastrointestinal tract. The biphasic test used in this work effectively differentiated various ABT-072 formulations derived from conventional and enabling technologies. In vitro profiles of these formulations indicate a complex interplay among the 3 competitive kinetic processes including dissolution, precipitation, and partition in the aqueous media. The relative amount of drug partitioned into the organic phase (i.e., octanol) from different formulations was found to be directly related to their in vivo exposures observed in both dogs and human subjects, respectively. An in vitro-in vivo relationship was obtained between ABT-072 concentrations in octanol at t = 2 h from these formulations and the relative bioavailabilities in dogs and human subjects. This work revealed the significance of polymeric precipitation inhibition by sustaining a supersaturated state of ABT-072 and its impact on in vivo exposure in human subjects.
Synthesis and Biological Characterization of Aryl Uracil Inhibitors of Hepatitis C Virus NS5B Polymerase: Discovery of ABT-072, a trans-Stilbene Analog with Good Oral Bioavailability
J Med Chem 2018 Feb 8;61(3):1153-1163.PMID:29342358DOI:10.1021/acs.jmedchem.7b01630.
ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compound was identified during a medicinal chemistry effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compound permeability and solubility and provided much better pharmacokinetic properties in preclinical species. Replacement of the dihydrouracil in 1 with an N-linked uracil provided better potency in the genotype 1 replicon assay. Results from phase 1 clinical studies supported once-daily oral dosing with ABT-072 in HCV infected patients. A phase 2 clinical study that combined ABT-072 with the HCV protease inhibitor ABT-450 provided a sustained virologic response at 24 weeks after dosing (SVR24) in 10 of 11 patients who received treatment.
Current prospects for interferon-free treatment of hepatitis C in 2012
J Gastroenterol Hepatol 2013 Jan;28(1):38-45.PMID:23137126DOI:10.1111/jgh.12028.
Present interferon-based therapy for chronic hepatitis C is limited by both efficacy and tolerability. Telaprevir and boceprevir are the first two direct-acting antiviral drugs (DAAs) that inhibit hepatitis C virus replication to be licensed for use in conjunction with pegylated interferon and ribavirin. Numerous other DAAs are in clinical development, and phases 2 and 3 trials are evaluating interferon-free combination DAA therapy. Interferon-free sustained virologic responses have now been achieved with combinations of asunaprevir and daclatasvir; sofosbuvir and ribavirin; sofosbuvir and daclatasvir; faldaprevir and BI207127; ABT-450, ritonovir and ABT-333; ABT-450, ritonovir and ABT-072; miracitabine, danoprevir and ritonavir; and alisporivir and ribavirin. Some drugs are genotype-specific in their activity, whereas others are pan-genotypic, and differential responses for the genotype 1 subtypes 1a and 1b have emerged with many DAA combinations. Viral breakthrough and resistance are important considerations for future trial design. The prospect of interferon-free combination DAA therapy for hepatitis C virus is now finally becoming a reality.
Current race in the development of DAAs (direct-acting antivirals) against HCV
Biochem Pharmacol 2014 Jun 15;89(4):441-52.PMID:24735613DOI:10.1016/j.bcp.2014.04.005.
The direct-acting antivirals (DAAs) currently in development for treatment of hepatitis C fall into four categories: (i) NS3/4A protease inhibitors: ABT-450/r, faldaprevir, asunaprevir, GS-9256, vedroprevir (GS-9451), danoprevir, MK-5172, vaniprevir, sovaprevir, ACH-2684, narlaprevir and simeprevir, in addition to those that are already developed [telaprevir (Incivek®) and boceprevir (Victrelis®)], (ii) NS5A protein inhibitors: ABT-267, daclatasvir, ledipasvir, ACH-2928, ACH-3102, PPI-668, AZD-7295, MK-8742, and GSK 2336805; (iii) NS5B (nucleoside-type) polymerase inhibitors: sofosbuvir (now approved by the FDA since 6 December 2013), GS-0938, mericitabine, VX-135, ALS 2158 and TMC 649128; (iv) NS5B (non-nucleoside-type) polymerase inhibitors: VX-222, ABT-072, ABT-333, deleobuvir, tegobuvir, setrobuvir, VCH-916, VCH-759, BMS-791325 and TMC-647055. Future drug combinations will likely exist of two or more DAAs belonging to any of the 4 categories, with the aim to achieve (i) pan-genotypic hepatitis C virus (HCV) activity, (ii) little or no risk for resistance; (iii) short duration (i.e. 12 weeks) of treatment, and (iv) a sustained viral response (SVR) and definite cure of the disease.