Islatravir (MK-8591)
(Synonyms: 2'-脱氧-4'-C-乙炔基-2-氟腺苷,MK-8591) 目录号 : GC32306
A nucleoside reverse transcriptase inhibitor
Cas No.:865363-93-5
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
EFdA is a nucleoside reverse transcriptase inhibitor (NRTI).1 It inhibits HIV-1 reverse transcriptase via multiple mechanisms. EFdA inhibits replication of the HIV-1 strain HIV-1 IIIb, the laboratory isolate HIV NL4-3, and the clinical isolate HIV-2 EHO in MT-4 cells (EC50s = 73, 50, and 98 pM, respectively).2 It is also active against drug-resistant HIV with EC50 values ranging from 0.23 to 23 nM in a multinuclear activation of a galactosidase indicator (MAGI) assay.3 EFdA (1 and 10 mg/kg per day) prevents infection with HIV JR-CSF in humanized mice.4
1.Michailidis, E., Huber, A.D., Ryan, E.M., et al.4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) inhibits HIV-1 reverse transcriptase with multiple mechanismsJ. Biol. Chem.289(35)24533-24548(2014) 2.Markowitz, M., and Sarafianos, S.G.4'-Ethynyl-2-fluoro-2'-deoxyadenosine, MK-8591: A novel HIV-1 reverse transcriptase translocation inhibitorCurr. Opin. HIV AIDS13(4)294-299(2018) 3.Kawamoto, A., Kodama, E., Sarafianos, S.G., et al.2'-deoxy-4'-C-ethynyl-2-halo-adenosines active against drug-resistant human immunodeficiency virus type 1 variantsInt. J. Biochem. Cell Biol.40(11)2410-2420(2008) 4.Stoddart, C.A., Galkina, S.A., Joshi, P., et al.Oral administration of the nucleoside EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine) provides rapid suppression of HIV viremia in humanized mice and favorable pharmacokinetic properties in mice and the rhesus macaqueAntimicrob. Agents Chemother.59(7)4190-4198(2015)
| Cas No. | 865363-93-5 | SDF | |
| 别名 | 2'-脱氧-4'-C-乙炔基-2-氟腺苷,MK-8591 | ||
| Canonical SMILES | OC[C@]1(C#C)[C@H](C[C@H](N2C=NC3=C2N=C(F)N=C3N)O1)O | ||
| 分子式 | C12H12FN5O3 | 分子量 | 293.25 |
| 溶解度 | DMSO: 20.83 mg/mL (71.03 mM; ultrasonic and adjust pH to 3 with HCl); Water: 3.57 mg/mL (12.17 mM; ultrasonic and warming and heat to 60°C) | 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 | 3.4101 mL | 17.0503 mL | 34.1006 mL |
| 5 mM | 0.682 mL | 3.4101 mL | 6.8201 mL |
| 10 mM | 0.341 mL | 1.705 mL | 3.4101 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。
Update and latest advances in antiretroviral therapy
Trends Pharmacol Sci 2022 Jan;43(1):16-29.PMID:34742581DOI:10.1016/j.tips.2021.10.004.
Since the first cases of AIDS appeared in 1981, human immunodeficiency virus type 1 (HIV-1) infection has reached pandemic proportions. Forty years later, research has led to the approval of more than 30 antiretroviral drugs, while combination therapies have turned HIV-1 infection into a chronic, but manageable disease. Still, drug toxicity and acquired and transmitted drug resistance remain as major threats to therapy success. In this review, we provide an overview on currently available anti-HIV drugs and the latest developments in antiretroviral therapy, focused on new antiretroviral agents acting on known and unexploited antiviral targets, prevention therapies aimed to improve available drug combinations, and research on new long-acting therapies, particularly those involving novel drug candidates such as lenacapavir or Islatravir.
Approved HIV reverse transcriptase inhibitors in the past decade
Acta Pharm Sin B 2022 Apr;12(4):1567-1590.PMID:35847492DOI:10.1016/j.apsb.2021.11.009.
HIV reverse transcriptase (RT) inhibitors are the important components of highly active antiretroviral therapies (HAARTs) for anti-HIV treatment and pre-exposure prophylaxis in clinical practice. Many RT inhibitors and their combination regimens have been approved in the past ten years, but a review on their drug discovery, pharmacology, and clinical efficacy is lacking. Here, we provide a comprehensive review of RT inhibitors (tenofovir alafenamide, rilpivirine, doravirine, dapivirine, azvudine and elsulfavirine) approved in the past decade, regarding their drug discovery, pharmacology, and clinical efficacy in randomized controlled trials. Novel RT inhibitors such as Islatravir, MK-8504, MK-8507, MK8583, IQP-0528, and MIV-150 will be also highlighted. Future development may focus on the new generation of novel antiretroviral inhibitors with higher bioavailability, longer elimination half-life, more favorable side-effect profiles, fewer drug-drug interactions, and higher activities against circulating drug-resistant strains.
Safety, tolerability, and pharmacokinetics of single- and multiple-dose administration of Islatravir (MK-8591) in adults without HIV
Clin Transl Sci 2021 Sep;14(5):1935-1944.PMID:34463432DOI:10.1111/cts.13048.
Islatravir (MK-8591) is a nucleoside analogue in development for the treatment and prevention of HIV-1. Two phase 1 trials were conducted during initial evaluation of islatravir: rising single doses (Study 1) and rising multiple doses (Study 2) of oral islatravir in male and female participants without HIV (aged 18-60 years). Safety, tolerability, and pharmacokinetics of islatravir (plasma) and islatravir-triphosphate (peripheral blood mononuclear cells) were assessed. In Study 1, 24 participants, assigned to 1 of 3 panels, received alternating single doses of islatravir in a fasted state from 5 mg to 400 mg, or placebo, over 3 dosing periods; a 30 mg dose was additionally assessed following a high-fat meal. In Study 2, 8 participants per dose received 3 once-weekly doses of 10, 30, or 100 mg islatravir or placebo in a fasted state. For each panel in both trials, 6 participants received active drug and 2 received placebo. Islatravir was generally well-tolerated, with no serious adverse events or discontinuations due to adverse events. Islatravir was rapidly absorbed (median time to maximum plasma concentration 0.5 hours); plasma half-life was 49-61 h; intracellular islatravir-triphosphate half-life was 118-171 h. Plasma exposure increased in an approximately dose-proportional manner; there was no meaningful food effect. There was a modest degree of intracellular islatravir-triphosphate accumulation after multiple weekly dosing. After single oral doses of islatravir greater than or equal to 5 mg, intracellular islatravir-triphosphate levels were comparable to levels associated with efficacy in preclinical studies. These results warrant continued clinical investigation of islatravir.
Safety, pharmacokinetics, and antiretroviral activity of Islatravir (ISL, MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor, following single-dose administration to treatment-naive adults infected with HIV-1: an open-label, phase 1b, consecutive-panel trial
Lancet HIV 2020 Mar;7(3):e164-e172.PMID:31911147DOI:10.1016/S2352-3018(19)30372-8.
Background: Islatravir (also known as ISL and MK-8591) is a unique nucleoside reverse transcriptase translocation inhibitor in clinical development for treatment of people with HIV-1 infection. In preclinical studies, intracellular islatravir-triphosphate exhibits a long half-life and prolonged virological effects. In this study, we aimed to assess Islatravir safety, pharmacokinetics, and antiretroviral activity in treatment-naive adults with HIV-1 infection. Methods: This open-label, consecutive-panel, phase 1b trial was done at Charit茅 Research Organisation (Berlin, Germany) and included men and women (aged 18-60 years, inclusive) with HIV-1 infection who were ART naive. Participants were required to have plasma HIV-1 RNA counts of at least 10 000 copies per mL within 30 days before the trial treatment phase, without evidence of resistance to nucleoside reverse transcriptase inhibitors. Participants were enrolled in one of five consecutive dosing panels, receiving a single oral dose of Islatravir (0路5-30 mg). The primary outcomes were safety and tolerability of Islatravir and change from baseline in HIV-1 plasma RNA; secondary outcomes were Islatravir plasma and islatravir-triphosphate intracellular pharmacokinetics. We obtained descriptive safety and pharmacokinetics statistics, and estimated efficacy results from a longitudinal data analysis model. This study is registered with ClinicalTrials.gov, NCT02217904, and EudraCT, 2014-002192-28. Findings: Between Sept 17, 2015, and May 11, 2017, we enrolled 30 participants (six per panel). Islatravir was generally well tolerated. 27 (90%) participants had 60 adverse events after receipt of drug, of which 21 (35%) were deemed to be drug related. The most common (n>1) drug-related adverse events were headache (in nine [30%] participants) and diarrhoea (in two [7%]). No serious adverse events were reported, and no participants discontinued due to an adverse event. Plasma Islatravir pharmacokinetics and intracellular islatravir-triphosphate pharmacokinetics were approximately dose proportional. The islatravir-triphosphate intracellular half-life was 78路5-128路0 h. Least-squares mean HIV-1 RNA at 7 days after dose decreased from 1路67 log10 copies per mL (95% CI 1路42-1路92) at 10 mg dose to 1路20 log10 copies per mL (0路95-1路46) at 0路5 mg dose. No genetic changes consistent with development of viral resistance were detected. Interpretation: Single doses of Islatravir as low as 0路5 mg significantly suppressed HIV-1 RNA by more than 1路0 log at day 7 in treatment-naive adults with HIV-1 infection and were generally well tolerated, supporting the further development of Islatravir as a flexible-dose treatment for individuals with HIV-1 infection. Funding: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, NJ, USA.
A Phase 1 Study to Evaluate the Drug Interaction Between Islatravir (MK-8591) and Doravirine in Adults Without HIV
Clin Drug Investig 2021 Jul;41(7):629-638.PMID:34151413DOI:10.1007/s40261-021-01046-1.
Background and objectives: Islatravir (MK-8591) is a novel nucleoside analogue in development for the treatment and prevention of HIV-1 infection. Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1 infection. This study evaluated the pharmacokinetics, safety, and tolerability of islatravir and doravirine coadministration in a double-blind, placebo-controlled, randomized, fixed-sequence study. Methods: Adult participants without HIV infection were administered oral doravirine 100 mg (n = 10) or placebo (n = 4) once daily (QD) for 5 days, immediately followed by oral islatravir 2.25 mg (n = 10) or placebo QD (n = 4) for 14 days; islatravir 2.25 mg and doravirine 100 mg QD, or placebo QD, were then coadministered for 5 days. Pharmacokinetic and safety data were collected. Results: Doravirine geometric least-squares mean ratios (90% confidence intervals (CIs)) of (doravirine + islatravir)/doravirine for the area under the plasma drug concentration-time curve over 24 h (AUC0-24h), maximum plasma concentration (Cmax), and plasma concentration at 24 h post-dose (C24h) were not meaningfully impacted. Islatravir geometric least-squares mean ratios (90% CI) of (islatravir + doravirine)/islatravir for AUC0-24h and Cmax were both close to unity, 1.06 (1.01, 1.12) and 1.08 (0.91, 1.27), respectively. All study regimens were generally well tolerated. Conclusion: These results indicate that coadministration of islatravir and doravirine had no clinically meaningful effect on the pharmacokinetics of either drug, and support further clinical investigation of islatravir in combination with doravirine for the treatment of HIV-1 infection.