N-[5-[[2-(2,6-dimethylphenoxy)acetyl]amino]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide | 192725-17-0

• 物质功能分类: 原料药 - 人工合成抗感染类药 - 抗病毒类药
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-[5-[[2-(2,6-dimethylphenoxy)acetyl]amino]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide
• CAS: 192725-17-0
• 化学式: C₃₇H₄₈N₄O₅
• 分子量: 628.8
• InChiKey: KJHKTHWMRKYKJE-UHFFFAOYSA-N

物化性质

• 熔点：
  255.2-260.6 °F (124—127°C)
• 沸点：
  924.1±65.0 °C(Predicted)
• 密度：
  1.163±0.06 g/cm3(Predicted)
• 溶解度：
  在DMSO中的溶解度为20mg/mL，澄清
• 颜色/状态：
  Colorless solid from ethyl acetone
• 蒸汽压力：
  3.4X10-24 mm Hg at 25 °C (est)
• 稳定性/保质期：

  Based on the provided data, 18 months shelf life has been granted for the soft capsules when stored within their container at 5 °C with the option for room temperature storage after dispensing to the patients for up to 42 days. ... Based on the preliminary data, 18 months shelf life is acceptable when the oral solution is stored within its container at 5 °C, with the option for room temperature storage after dispensing to the patients for up to 42 days.

• 分解：
  When heated to decomposition, material emits toxic fumes.

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  46
• 可旋转键数：
  15
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  120
• 氢给体数：
  4
• 氢受体数：
  5

ADMET

代谢

洛匹那韦在大鼠、狗和人体内主要通过肝脏的CYP3A4同工酶代谢。在大鼠和狗口服给药后，粪便中的放射性物质大部分是未改变的母化合物。尽管在大鼠、狗和人体之间代谢物模式有相似之处，但定性和定量差异被观察到。洛匹那韦的代谢对利托那韦的抑制敏感，这与在大鼠中观察到的利托那韦对洛匹那韦代谢清除的抑制相一致。

Lopinavir was metabolised in rat, dog and human primarily by hepatic CYP3A4 isoenzymes. Radioactivity in rat and dog faeces consisted largely of unchanged parent compound after oral administration. Although there were similarities in metabolite pattern between rat, dog and human, qualitative and quantitative differences were observed. The metabolism of lopinavir was sensitive to inhibition of ritonavir, which is in accordance with the inhibition of metabolic clearance of lopinavir by ritonavir observed in the rat.

来源:Hazardous Substances Data Bank (HSDB)

代谢

体外实验表明，洛匹那韦主要通过肝脏微粒体的氧化代谢进行。洛匹那韦主要通过肝脏细胞色素P450系统的CYP3A同工酶广泛代谢。利托那韦是一种强效的CYP3A抑制剂，可以抑制洛匹那韦的代谢，因此增加洛匹那韦的血浆水平。在人体中进行的(14)C-洛匹那韦研究表明，单次服用400/100毫克凯勒特拉剂量后，89%的血浆放射性活性归因于母药。在人体中至少已经识别出13种洛匹那韦的氧化代谢物。已经显示利托那韦可以诱导代谢酶，导致其自身代谢的诱导。在多次给药期间，洛匹那韦的预给药浓度随时间下降，在大约10到16天后稳定。

In vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolized by the hepatic cytochrome P450 system, almost exclusively by the CYP3A isozyme. Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism of lopinavir, and therefore increases plasma levels of lopinavir. A (14)C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg Kaletra dose was due to parent drug. At least 13 lopinavir oxidative metabolites have been identified in man. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilizing after approximately 10 to 16 days.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用概要：洛匹那韦在母乳中以低水平出现，可以在一些母乳喂养婴儿的血清中找到。尽管洛匹那韦与直接给婴儿使用时影响肾上腺功能有关，但这一效应与剂量相关。母乳中少量的洛匹那韦没有明确导致婴儿不良反应。在美国和其他可以获得清洁水源和负担得起的替代喂养的国家，建议携带HIV的母亲不要母乳喂养婴儿，以避免产后HIV-1感染传播。通过抗逆转录病毒疗法实现和维持病毒抑制，可以将母乳传播风险降低到1%以下，但并非零。携带HIV且在抗逆转录病毒疗法下维持不可检测病毒载量的个体如果选择母乳喂养，应在这一决定中得到支持。 ◉ 母乳喂养婴儿的影响：一项研究比较了三组接受齐多夫定预防母婴传播HIV感染的后遗症预防的婴儿的严重贫血发生率。在6个月大之前，接受HAART的母亲喂养的母乳喂养婴儿的严重贫血发生率（7.4%）高于仅接受齐多夫定的母亲喂养的母乳喂养婴儿（5.3%）。配方奶喂养的婴儿的严重贫血发生率最低（2.5%）。贫血通常对铁剂和多种维生素补充以及停止使用齐多夫定反应良好。 在乌干达进行的一项非盲研究中，比较了接受基于依非韦伦600毫克每日一次或洛匹那韦400毫克加利托那韦100毫克每日两次的母乳喂养期间抗逆转录病毒疗法的HIV阳性母亲和她们的母乳喂养婴儿的结果。所有母亲接受拉米夫定150毫克，齐多夫定300毫克每日两次和甲氧苄啶-磺胺甲恶唑每日一次。所有婴儿接受齐多夫定预防1周或奈韦拉平预防6周，以及从6周大开始到断奶后6周的甲氧苄啶-磺胺甲恶唑。几乎所有的婴儿在6个月大之前都是纯母乳喂养，大约73%的婴儿在12个月大之前部分母乳喂养。两组婴儿在住院或不良事件（包括贫血、中性粒细胞减少或死亡）方面没有统计学差异。 在9名（喂养程度未说明）母乳喂养婴儿中，母亲正在服用洛匹那韦400毫克加利托那韦100毫克每日两次作为多药治疗HIV感染的一部分，研究者在1、3和6个月大时没有注意到不良影响，也没有母亲报告。 ◉ 对泌乳和母乳的影响：在接受高度活跃抗逆转录病毒疗法的男性中报告了男性乳房发育。男性乳房发育最初是单侧的，但在大约一半的病例中进展为双侧。没有观察到血清催乳素的变化，即使继续使用该方案，通常也会在一年内自发解决。一些病例报告和体外研究表明，蛋白酶抑制剂可能会导致一些男性患者出现高催乳素血症和乳汁分泌过多，尽管这一点存在争议。这些发现对哺乳母亲的相关性尚不清楚。已建立泌乳的母亲催乳素水平可能不会影响她哺乳的能力。

◉ Summary of Use during Lactation:Lopinavir appears in breastmilk in low levels and can be found in the serum of some breastfed infants. Although lopinavir has been associated with impaired adrenal gland function when given directly to infants, the effect is dose related. No adverse infant effects have been clearly caused by the small amounts of lopinavir in breastmilk. In the US and other countries where access to clean water and affordable replacement feeding are available, it is recommended that mothers living with HIV not breastfeed their infants to avoid postnatal transmission of HIV-1 infection. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. Ritonavir used as a booster has been studied in several studies of breastfeeding mothers. It is excreted into milk in measurable concentrations and low levels can be found in the blood of some breastfed infants. No reports of adverse reactions in breastfed infants have been reported. For more information, refer to the LactMed record on ritonavir. ◉ Effects in Breastfed Infants:A study compared the rates of severe anemia in 3 groups of infants who received postpartum prophylaxis with zidovudine for prevention of maternal-to-child transmission of HIV infection. Through 6 months of age, breastfed infants whose mothers received HAART had a higher rate of severe anemia (7.4%) than breastfed infants whose mothers received only zidovudine (5.3%). Formula-fed infants had the lowest rate of severe anemia (2.5%). The anemia generally responded well to iron and multivitamin supplementation, and discontinuation of zidovudine. An unblinded study in Uganda compared the outcomes of breastfed infants and their HIV-positive mothers who were randomized to receive antiretroviral therapy that was based either on efavirenz 600 mg once daily or lopinavir 400 mg plus ritonavir 100 mg twice daily during breastfeeding. All mothers received lamivudine 150 mg, zidovudine 300 mg twice daily and trimethoprim-sulfamethoxazole once daily. All infants received prophylaxis with either zidovudine for 1 week or nevirapine for 6 weeks, plus trimethoprim-sulfamethoxazole from 6 weeks of age to 6 weeks after weaning. Almost all of the infants were exclusively breastfed until 6 months of age and about 73% were partially breastfed until 12 months of age. There was no statistical difference in hospitalizations or adverse events including anemia, neutropenia or deaths among infants in the two groups. Among 9 breastfed (extent not stated) infants whose mothers were taking lopinavir 400 mg with ritonavir 100 mg twice daily as part of a multi-drug treatment for HIV infection, no adverse effects were noted by investigators or reported by mothers at 1, 3 and 6 months of age. ◉ Effects on Lactation and Breastmilk:Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen. Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients, although this has been disputed. The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

可能存在与胺碘酮、苄普地尔（在美国已不再商业销售）、利多卡因（系统性）和奎尼丁（提高抗心律失常药物的血浆浓度）的药代动力学相互作用。小心使用。如果与洛匹那韦/利托那韦同时使用，监测抗心律失常药物的血浆浓度。

Possible pharmacokinetic interaction with amiodarone, bepridil (no longer commercially available in the US), lidocaine (systemic), and quinidine (increased plasma concentrations of the antiarrhythmic agent). Use with caution. Monitor plasma concentrations of the antiarrhythmic agents if used concomitantly with lopinavir/ritonavir.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

药代动力学相互作用（增加盐酸阿夫唑嗪血药浓度）可能会导致低血压。洛匹那韦/利托那韦与盐酸阿夫唑嗪的联合使用是禁忌的。

Pharmacokinetic interaction (increased alfuzosin plasma concentrations) may result in hypotension. Concomitant use of lopinavir/ritonavir and alfuzosin is contraindicated.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

洛匹那韦/利托那韦诱导糖苷酸化（即，增加某些通过糖苷酸化代谢的药物的生物转化）。

Lopinavir/ritonavir induces glucuronidation (i.e., increases biotransformation of some drugs metabolized by glucuronidation).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

洛匹那韦和利托那韦的固定组合（洛匹那韦/利托那韦）抑制细胞色素P-450（CYP）同工酶；与经CYP3A代谢的药物可能发生药代动力学相互作用（改变经CYP3A代谢的药物的代谢）。与一些CYP3A底物的药物同时使用是禁忌的；与其他CYP3A底物的药物同时使用可能需要调整剂量或进行额外的监测。洛匹那韦和利托那韦由CYP3A代谢；与抑制或诱导CYP3A的药物可能发生药代动力学相互作用（改变洛匹那韦的代谢）。

The fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) inhibits the cytochrome P-450 (CYP) isoenzyme; potential pharmacokinetic interactions with drugs metabolized by CYP3A (altered metabolism of the drug metabolized by CYP3A). Concomitant use with some drugs that are CYP3A substrates is contraindicated; concomitant use with other drugs that are CYP3A substrates may require dosage adjustment or additional monitoring. Lopinavir and ritonavir are metabolized by CYP3A; potential pharmacokinetic interactions with drugs that inhibit or induce CYP3A (altered metabolism of lopinavir).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

稳态时，洛匹那韦大约有98-99%与血浆蛋白结合。洛匹那韦与α-1-酸性糖蛋白（AAG）和白蛋白都有结合，但它对AAG的亲和力更高。在稳态下，洛匹那韦的蛋白结合在观察到400/100毫克克磊罗（KALETRA）每日两次的浓度范围内保持恒定，并且在健康志愿者和HIV-1阳性患者之间相似。

At steady state, lopinavir is approximately 98-99% bound to plasma proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin; however, it has a higher affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of observed concentrations after 400/100 mg KALETRA twice daily, and is similar between healthy volunteers and HIV-1 positive patients.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在对HIV-1阳性受试者（n = 19）进行的药代动力学研究中，连续3周每天两次随餐服用400/100毫克KALETRA，产生了洛匹那韦的平均峰血浆浓度（Cmax）为9.8 ± 3.7微克/毫升，大约在给药后4小时达到。给药前早晨剂量的平均稳态谷浓度为7.1 ± 2.9微克/毫升，给药间隔内的最低浓度为5.5 ± 2.7微克/毫升。12小时给药间隔内洛匹那韦的AUC平均为92.6 ± 36.7微克*小时/毫升。洛匹那韦与利托那韦共同配方的绝对生物利用度在人体中尚未确定。在非空腹条件下（500千卡，25%来自脂肪），KALETRA共同配方的胶囊和口服溶液给药后洛匹那韦的浓度相似。在空腹条件下给药时，KALETRA口服溶液的洛匹那韦平均AUC和Cmax比胶囊配方低22%。

In a pharmacokinetic study in HIV-1 positive subjects (n = 19), multiple dosing with 400/100 mg KALETRA twice daily with food for 3 weeks produced a mean SD lopinavir peak plasma concentration (Cmax) of 9.8 + or - 3.7 ug/mL, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 7.1 + or - 2.9 ug/mL and minimum concentration within a dosing interval was 5.5 + or - 2.7 ug/mL. Lopinavir AUC over a 12 hour dosing interval averaged 92.6 + or - 36.7 ug*h/mL. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established. Under nonfasting conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of KALETRA co-formulated capsules and oral solution. When administered under fasting conditions, both the mean AUC and Cmax of lopinavir were 22% lower for the KALETRA oral solution relative to the capsule formulation.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

洛匹那韦和利托那韦在大鼠乳汁中有分布；目前尚不清楚这些药物是否分布到人乳中。

Lopinavir and ritonavir are distributed into milk in rats; it is not known whether the drugs are distributed into human milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Kaletra每日一次的药代动力学已在未经抗逆转录病毒治疗的HIV-1感染受试者中进行了评估。Kaletra 800/200 mg与恩曲他滨200 mg和替诺福韦DF 300 mg联合使用，作为每日一次方案的一部分。800/200 mg的Kaletra在食物伴随下每日一次多次给药4周（n = 24），产生了平均±3.7 SD的洛匹那韦峰浓度（Cmax）为11.8 ± 3.7微克/毫升，大约在给药后6小时出现。早晨剂量前洛匹那韦的平均稳态谷浓度为3.2 ± 3.7 2.1微克/毫升，给药间隔内的最低浓度为1.7 ± 3.7 1.6微克/毫升。24小时给药间隔内洛匹那韦的AUC平均为154.1 ± 3.7 61.4微克*小时/毫升。

The pharmacokinetics of once daily Kaletra have been evaluated in HIV-1 infected subjects naive to antiretroviral treatment. Kaletra 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir DF 300 mg as part of a once daily regimen. Multiple dosing of 800/200 mg Kaletra once daily for 4 weeks with food (n = 24) produced a mean + or - 3.7 SD lopinavir peak plasma concentration (Cmax) of 11.8 + or - 3.7 ug/mL, occurring approximately 6 hours after administration. The mean steady-state lopinavir trough concentration prior to the morning dose was 3.2 + or - 3.7 2.1 ug/mL and minimum concentration within a dosing interval was 1.7 + or - 3.7 1.6 ug/mL. Lopinavir AUC over a 24 hour dosing interval averaged 154.1 + or - 3.7 61.4 ug* h/mL.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  29335990
• 危险品运输编号：
  NONH for all modes of transport
• 危险品标志：
  Xi
• WGK Germany：
  3
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  hygroscopic, stored at -20°C in a freezer under an inert atmosphere

制备方法与用途

概述

洛匹那韦，化学名称为(2S)-N-[(2R,4S,5S)-5-[[2-(2,6-二甲基苯氧基)乙酰]氨基]-4-羟基-1,6-二苯基-己-2-基]-3-甲基-2-(2-氧代-1,3-二氮杂环己-1-基)丁酰胺，是雅培公司基于利托那韦设计改进的新一代HIV蛋白酶抑制剂。可用于生化实验、合成实验等。

生物活性

洛匹那韦（Lopinavir）是一种有效的HIV蛋白酶抑制剂，Ki为1.3 pM。它与突变型HIV蛋白酶(V82A, V82F 和 V82T)结合时，分别表现出4.9 pM、3.7 pM和 3.6 pM的Ki值。0.5 nM Lopinavir可抑制93%野生型HIV蛋白酶活性。在MT4细胞中，Lopinavir抑制HIV蛋白酶活性的EC50分别为102 nM 和17 nM。

洛匹那韦/利托那韦片

洛匹那韦/利托那韦片是将洛匹那韦与利托那韦两个药物组成的复方制剂。两者都是病毒反转录抑制剂，其中洛匹那韦为主药，通过与病毒蛋白酶结合使得产生的病毒颗粒不成熟且无传染性；而利托那韦可抑制肝脏对洛匹那韦的代谢，从而提高洛匹那韦血药浓度，发挥协同作用。

国家卫健委办公厅、国家中医药管理局办公室在2020年1月27日发布的《新型冠状病毒感染的肺炎诊疗方案》（试行第四版）中指出，在抗新型冠状病毒治疗中可试用洛匹那韦/利托那韦等药物治疗。洛匹那韦（Lopinavir）和利托那韦（Ritonavir）均为蛋白酶抑制剂类抗艾滋病药物，通过阻断Gag-Pol聚蛋白的分裂，产生未成熟、无感染力的病毒颗粒，达到抑制病毒复制的作用。

由于肠上皮细胞管腔表面高表达的P-gp和MRP2介导的外排泵作用、肝脏中CYP3A4酶的广泛代谢作用，以及洛匹那韦本身较低的水溶性（40 mg/mL），洛匹那韦的口服生物利用度较差。利托那韦不仅是蛋白酶抑制剂，而且对CYP450酶（CYP3A4是其同工酶）有较强的抑制作用，用小剂量的利托那韦与洛匹那韦竞争性结合CYP3A4，可以提高洛匹那韦在体内的生物利用度。

生物活性

Lopinavir与突变型HIV蛋白酶(V82A, V82F 和 V82T)结合时表现出不同的Ki值：分别为4.9 pM、3.7 pM和 3.6 pM。0.5 nM Lopinavir可抑制93%野生型HIV蛋白酶活性。Lopinavir作用于MT4细胞，在有或无50% HS存在时，其抑制HIV蛋白酶的EC50分别为102 nM 和17 nM。Lopinavir在肝微粒中转换成一些代谢物，初级代谢物为M-3和M-4，这种作用具有NADPH依赖性。

此外，Lopinavir是有效的Rb23抑制剂，在Caco-2细胞层中的IC50值为1.7 mM。处理LS 180V 细胞72小时后，细胞内Rb23含量降低。Lopinavir作用于LS 180V 细胞，诱导P-糖蛋白免疫反应性蛋白和信使RNA水平。在人肝微粒体中，Lopinavir抑制CYP3A的IC50为7.3 mM，并且也微弱抑制人类CYP1A2、2B6、2C9、2C19、2D6。

体内研究

洛匹那韦按10 mg/kg剂量口服给药大鼠，其血药浓度（Cmax）达到0.8 μg/mL，口服生物有效性为25%。

文献信息

• [EN] PARTICLES CONTAINING BRANCHED POLYMERS<br/>[FR] PARTICULES CONTENANT DES POLYMÈRES RAMIFIÉS
  申请人：UNIV LIVERPOOL

  公开号：WO2016009227A1

  公开（公告）日：2016-01-21

  Particles comprising a branched polymer and either a block copolymer or a linear dendritic hybrid represent a category of useful materials. They may be used in for example drug delivery applications. They may be prepared by a method comprising the steps of: dissolving the branched polymer and block copolymer or linear dendritic hybrid, and optionally other component(s),in a solvent to form a solution; adding said solution to a different liquid; and removing said solvent to form a dispersion of co-precipitated particles.

  由支化聚合物和块共聚物或线性树状混合物组成的微粒代表一类有用材料。它们可以用于例如药物传递应用。它们可以通过以下步骤制备：将支化聚合物和块共聚物或线性树状混合物以及可选的其他组分溶解在溶剂中形成溶液；将该溶液加入到另一种液体中；并去除溶剂以形成共沉淀微粒的分散体。
• Pharmaceutical Formulations
  申请人：Alani Laman

  公开号：US20090053305A1

  公开（公告）日：2009-02-26

  Improved pharmaceutical compositions are provided comprising one or more solubilized HIV protease inhibiting compounds having improved solubility properties in a medium and/or long chain fatty acid, or mixtures thereof, a pharmaceutically acceptable alcohol, and water.

  提供了改进的药物组合物，其中包括一种或多种在介质中具有改进的溶解性质的溶解的HIV蛋白酶抑制剂化合物和/或中长链脂肪酸或其混合物，以及药用可接受的醇和水。
• Pharmaceutical formulations
  申请人：Alani Laman

  公开号：US20070032436A1

  公开（公告）日：2007-02-08

  Improved pharmaceutical compositions are provided comprising one or more solubilized HIV protease inhibiting compounds having improved solubility properties in a medium and/or long chain fatty acid, or mixtures thereof, a pharmaceutically acceptable alcohol, and water.

  提供了改进的制药组合物，其中包括一种或多种溶解的HIV蛋白酶抑制剂化合物，在中长链脂肪酸或其混合物中具有改进的溶解性能，以及药学上可接受的酒精和水。
• Oligomer-Protease Inhibitor Conjugates
  申请人：Riggs-Sauthier Jennifer

  公开号：US20110269677A1

  公开（公告）日：2011-11-03

  The invention provides protease inhibitors that are chemically modified by covalent attachment of a water-soluble oligomer. A conjugate of the invention, when administered by any of a number of administration routes, exhibits characteristics that are different from the protease inhibitors not attached to the water-soluble oligomer.

  该发明提供了通过共价连接水溶性寡聚体进行化学修饰的蛋白酶抑制剂。该发明的结合物在通过任何一种给药途径进行给药时，表现出与未连接水溶性寡聚体的蛋白酶抑制剂不同的特性。
• OLIGOMER-PROTEASE INHIBITOR CONJUGATES
  申请人：NEKTAR THERAPEUTICS

  公开号：US20140045770A1

  公开（公告）日：2014-02-13

  The invention provides small molecule drugs that are chemically modified by covalent attachment of a water-soluble oligomer. A conjugate of the invention, when administered by any of a number of administration routes, exhibits characteristics that are different from the small molecule drug not attached to the water-soluble oligomer.

  本发明提供了通过共价结合水溶性寡聚物进行化学修饰的小分子药物。本发明的结合物在通过任何一种给药途径给予时，表现出与未连接水溶性寡聚物的小分子药物不同的特性。