Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcriptase (RT) (IC₅₀ = 0.26 μM for recombinant HIV-1 RT)
DNA polymerase α (IC₅₀ > 440 μM)
DNA polymerase δ (IC₅₀ > 550 μM)

当剂量大于 100 μM 时，地拉韦啶对 H9 和 PBMC 细胞具有 50% 的细胞毒性。 100 μM 时，地拉韦啶导致外周血淋巴细胞活力下降不到 8%，表明其细胞毒性适中 [1]。地拉韦啶的 IC50 值为 0.26 μM，可抑制野生型形式的 HIV-1 逆转录酶 (RT)。它还抑制用 Y181C 和 K103N 替代的 RT，IC50 值分别为 8.32 uM 和 7.7 uM [1]。

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U-90152 抑制重组HIV-1逆转录酶，IC₅₀为0.26 μM，对细胞DNA聚合酶α和δ的选择性很高（IC₅₀分别 > 440 μM和 > 550 μM）。
它在外周血淋巴细胞中抑制了25株原发性HIV-1分离株的复制，平均ED₅₀为0.066 ± 0.137 μM，包括对AZT或ddI具有高度耐药性的变异株。
在100 μM浓度下，它导致外周血淋巴细胞存活率降低小于8%。
在MT-2细胞中，它抑制HIV-1诱导的合胞体形成，ED₅₀约为10 nM。
在感染单核细胞嗜性HIV-1_JR-FL的原代单核-巨噬细胞培养物中，其ED₅₀约为20 nM。
在3 μM浓度下，它能完全阻止HIV-1_IIIB在MT-4细胞共培养体系中的传播；与0.5 μM AZT联用时，也能完全阻止病毒传播。
它对HIV-1 RT突变体Y181C（IC₅₀ = 8.32 μM）和K103N（IC₅₀ = 7.70 μM）仍保持抑制活性。 [1]

甲磺酸地拉韦啶 (U 90152) 是一种小循环成分，可快速吸收和消化。它以 10 mg/kg、200 mg/kg 或 250 mg/kg 的单剂量口服给药。在 CD-1 小鼠中，其代谢为脱烷基阿维啶的能力受到限制或阻碍（PK 研究），并且其代谢动力学是非线性的 [1]。

使用高纯度的酶，通过先前描述的方法测定了U-90152对源自HIV-1_IIIB的重组异源二聚体HIV-1 RT的抑制。使用poly(dA)-oligod(dT)作为模板-引物，并在聚合酶δ测定中包含增殖细胞核抗原，测定了对DNA聚合酶α和δ的抑制。通过定点诱变制备了耐药突变RT（Y181C、K103N），克隆到表达质粒中，通过金属亲和层析纯化为p66同源二聚体，并在抑制剂存在下测定了它们的RNA依赖性DNA聚合酶活性。 [1]

在MT-2细胞和外周血淋巴细胞中测定了对HIV-1_IIIB的抗病毒活性。MT-2细胞感染HIV-1_IIIB，洗涤后与药物共培养4天；通过计数合胞体确定ED₅₀。PBL以类似方式感染并与药物共培养6天；通过测量上清液p24抗原水平评估病毒复制。
使用标准化方案测试了对25株临床分离株的敏感性：感染PBL并与药物共培养，测量p24水平。
通过将植物血凝素刺激的正常PBL与0至100 μM U-90152共培养7天，然后进行细胞计数并通过台盼蓝排斥法测定活力，来评估细胞毒性。
在原代单核-巨噬细胞培养物中确定了对单核细胞嗜性HIV-1_JR-FL的活性。
通过在药物存在下，将HIV-1_IIIB感染的MT-4细胞与1000倍过量的未感染MT-4细胞共培养，来评估对病毒传播的抑制。定期用含新鲜药物的培养基稀释培养物。通过合胞体形成、p24抗原水平和细胞活力监测病毒传播。 [1]

Absorption, Distribution and Excretion
Excretion: Fecal excretion: In healthy volunteers, after taking 330 mg three times daily, 44% of the drug was excreted in the feces. Renal excretion: In healthy volunteers, after taking 330 mg three times daily, 51% of the drug was excreted in the kidneys. Less than 5% of the drug was excreted unchanged in the urine. Delavoridine is primarily distributed in the plasma. Delavoridine is well absorbed, especially at pH values below 2.0. Oral absorption of delavoridine mesylate is rapid, reaching peak plasma concentration approximately 1 hour after administration. Following oral administration of 400 mg deraviridine mesylate three times daily in HIV-infected adults, the mean steady-state peak plasma concentration was 15.98 μg/mL (range: 0.91–45.66 μg/mL), the mean trough plasma concentration was 6.85 μg/mL (range: 0.05–20.55 μg/mL), and the mean AUC was 82.19 μg/h/mL. For more complete data on absorption, distribution, and excretion of deraviridine mesylate (8 items in total), please visit the HSDB record page. Metabolites/Metabolites: Deraviridine is extensively bound to plasma proteins and is primarily metabolized via CYP3A4. The main metabolic pathway is N-dealkylation. Significant inter-individual variability exists in plasma deraviridine concentrations, which is related to differences in CYP3A activity. The cerebrospinal fluid to plasma concentration ratio is 0.02.
Delavedin undergoes extensive metabolism in mice, including amide bond cleavage, N-dealkylation, pyridine ring C-6' hydroxylation, and pyridine ring cleavage. These metabolic pathways were determined by mass spectrometry and/or ¹H and ¹³C nuclear magnetic resonance spectroscopy. At low doses, N-dealkylation and amide bond cleavage are the predominant metabolic pathways; however, at high doses and after repeated administration, amide bond cleavage becomes the predominant metabolic pathway as the bioconversion of dealkylated delavedin reaches saturation or is inhibited.
Biological Half-Life
The apparent plasma half-life of delavedin increases with increasing dose. In adults, the mean plasma half-life after three daily doses of 400 mg delavedin is 5.8 hours (range: 2–11 hours).
Plasma Clearance: The mean clearance time after three daily doses of 400 mg is 5.8 hours (range: 2–11 hours). The apparent half-life increases with increasing dosage.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Delapiridine has been discontinued in the United States. There is currently no publicly available information regarding the use of delapiridine during lactation. Use of delapiridine during lactation is not recommended. Achieving and maintaining viral suppression through antiretroviral therapy can reduce the risk of transmission through breastfeeding to below 1%, but not zero. For HIV-infected individuals receiving antiretroviral therapy with a persistently low viral load below the detection limit, breastfeeding should be supported if they choose to do so. If viral load is not suppressed, pasteurized donor breast milk or formula is recommended.
◉ Effects on Breastfed Infants
No published information was found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information was found as of the revision date.

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U-90152 showed low cytotoxicity. At a concentration of 100 μM, it resulted in a decrease of less than 8% in the viability of phytohemagglutinin-stimulated peripheral blood lymphocytes cultured for 7 days. [1]

[1]. U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication. Antimicrob Agents Chemother. 1993 May;37(5):1127-31.

[2]. Metabolism of the HIV-1 Reverse Transcriptase Inhibitor Delavirdine In Mice. Research Article.

Delavoridine mesylate is the monomethylsulfonate salt of delavoridine, a non-nucleoside reverse transcriptase inhibitor with specific activity against HIV-1. Viral resistance develops rapidly when delavoridine is used alone; therefore, it (in mesylate form) is often used in combination with other antiretroviral drugs for the treatment of HIV infection. It is both an antiviral drug and an HIV-1 reverse transcriptase inhibitor. It contains delavoridine. Delavoridine mesylate is the mesylate salt form of delavoridine, a synthetic non-nucleoside reverse transcriptase inhibitor. Studies have shown that when used in combination with other antiretroviral drugs, this drug can reduce HIV viral load and increase CD4 white blood cell counts in patients. As an inhibitor of the cytochrome P450 system, delavoridine may lead to increased serum concentrations of co-administered protease inhibitors metabolized by the cytochrome P450 system. A potent non-nucleoside reverse transcriptase inhibitor with specific activity against HIV-1.

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Mechanism of Action
After entering the cell, delavide binds to the hydrophobic pocket of the p66 subunit of reverse transcriptase. This causes a conformational change in the enzyme, forming a stable, inactive form. The delavide-reverse transcriptase complex is stabilized by a hydrogen bond at lysine 103 residues and a strong hydrophobic interaction with proline 236 residues. The concentration of delavide required to inhibit cellular polymerase is much higher than the concentration required to inhibit reverse transcriptase.
Although the mechanism of delavide's antiviral activity is not fully elucidated, the drug inhibits the replication of human immunodeficiency virus type 1 (HIV-1) by interfering with the viral RNA and DNA polymerase activities of reverse transcriptase. HIV reverse transcriptase is crucial for viral replication; its activity occurs after the viral particle penetrates the cell membrane and releases the viral core, but before the virus enters the nucleus and integrates into the chromosome, it resides in the cytoplasm of the host cell. This enzyme is multifunctional, with three main activities: RNA-directed DNA polymerase, RNase H, and DNA-directed DNA polymerase. Reverse transcriptase uses viral RNA as a template to form the negative strand of viral DNA, thereby producing a double-stranded RNA:DNA hybrid (i.e., RNA-directed DNA polymerase function). The RNase H function of reverse transcriptase promotes viral RNA replication by degrading the RNA component in the RNA:DNA hybrid after RNA replication, leaving behind single-stranded viral DNA. Using the newly formed negative strand of viral DNA as a template, reverse transcriptase synthesizes the positive strand of viral DNA, converting the single-stranded viral DNA into a double-stranded proviral DNA form (i.e., DNA-directed DNA polymerase function). BHAP derivatives, including delavide, inhibit the polymerase function of reverse transcriptase but not its RNase H function. These drugs bind directly to heterodimeric HIV-1 reverse transcriptase, exerting antiviral effects as specific, non-competitive HIV-1 reverse transcriptase inhibitors. Non-nucleoside reverse transcriptase inhibitors act on different sites of reverse transcriptase, unlike nucleoside reverse transcriptase inhibitors (e.g., abacavir, didanoxin, lamivudine, stavudine, zalcitabine, zidovudine), and their mechanisms of action also differ. Unlike currently available non-nucleoside reverse transcriptase inhibitors, dideoxynucleoside antiretroviral drugs need to be converted into triphosphate metabolites within the cell. These metabolites then compete with naturally occurring deoxynucleoside triphosphates for reverse transcriptase incorporation into viral DNA, leading to premature termination of the viral DNA chain by preventing further 5'→3' phosphodiester bond formation. U-90152 is a novel biheteroarylpiperazine (BHAP) class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Its structure is similar to U-87201E, but it exhibits higher antiviral activity.
It binds to HIV-1 reverse transcriptase at the same site as other BHAP and NNRTI drugs (such as nevirapine) and has a high epigenetic affinity (~80 nM).
Its inhibitory mechanism is a non-competitive inhibition against template-primer and substrate.
It exhibits synergistic inhibition of HIV-1 replication. When used in combination with AZT.
Although HIV-1 variants carrying RT mutations (e.g., Y181C, K103N) may exhibit lower sensitivity, U-90152 still maintains significant activity against these variants compared to other non-nucleoside reverse transcriptase inhibitors (NNRTIs).
Clinical trials of U-90152 mesylate have been initiated. [1]

C22H28N6O3S.CH4O3S

552.66678

552.182

147221-93-0

Delavirdine;136817-59-9

441386

White to yellow solid powder

732ºC at 760mmHg

118-120ºC

396.5ºC

2.74E-21mmHg at 25°C

4.531

181.56

4

10

6

37

842

0

MEPNHSOMXMALDZ-UHFFFAOYSA-N

InChI=1S/C22H28N6O3S.CH4O3S/c1-15(2)24-19-5-4-8-23-21(19)27-9-11-28(12-10-27)22(29)20-14-16-13-17(26-32(3,30)31)6-7-18(16)25-20;1-5(2,3)4/h4-8,13-15,24-26H,9-12H2,1-3H3;1H3,(H,2,3,4)

methanesulfonic acid;N-[2-[4-[3-(propan-2-ylamino)pyridin-2-yl]piperazine-1-carbonyl]-1H-indol-5-yl]methanesulfonamide

Rescriptor; BHAP-U 90152; U-90152; BHAP U 90152; U90152; BHAP-U-90152; U 90152; DLV

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

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

DMSO : ≥ 40.3 mg/mL (~72.92 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (4.52 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (4.52 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (4.52 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。