N-((2S,4S,5S)-5-(2-(2,6-Dimethylphenoxy)acetamido)-4-hydroxy-1,6-diphenylhexan-2-yl)-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-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-((2S,4S,5S)-5-(2-(2,6-Dimethylphenoxy)acetamido)-4-hydroxy-1,6-diphenylhexan-2-yl)-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanamide
• 英文别名: N-[(2S,4S,5S)-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-QZKHDZGUSA-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同工酶进行代谢。口服给药后，大鼠和狗粪便中的放射性物质大部分为未改变的母化合物。尽管大鼠、狗和人体在代谢物模式上有相似之处，但定性和定量差异是观察到的。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抑制洛匹那韦代谢清除的情况一致。

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的细胞色素P450系统进行氧化代谢，几乎完全由CYP3A同种物酶代谢。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，从而提高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毫克克力芝剂量后，血浆中89%的放射性活性归因于母药。在人体中已经鉴定出至少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

• 肝毒性

洛匹那韦含有抗逆转录病毒方案的某些程度的血清转氨酶升高在很大一部分患者中发生。在中度至重度血清转氨酶水平升高（超过正常上限的5倍）的患者中，有3%至10%的人出现，尽管在HIV-HCV合并感染的患者中，这一比例可能会更高。这些升高通常无症状且自我限制，即使继续用药也可以解决。由于洛匹那韦/利托那韦导致的临床明显肝病是罕见的。症状或黄疸发作的潜伏期通常为1至8周，血清酶升高的模式从肝细胞到胆汁淤积或混合不等。损伤通常是自我限制的；然而，已有致命病例的报告。此外，启动基于洛匹那韦/利托那韦的高活性抗逆转录病毒治疗可能导致合并感染个体的慢性乙型或丙型肝炎加剧，通常在开始治疗后的2至12个月内出现，并伴有血清酶升高的肝细胞模式和血清乙型肝炎病毒（HBV）DNA或丙型肝炎病毒（HCV）RNA水平的增加。洛匹那韦治疗与几种核苷类似物逆转录酶抑制剂相关的乳酸酸中毒和急性脂肪肝没有明确的联系。

Some degree of serum aminotransferase elevations occur in a high proportion of patients taking lopinavir containing antiretroviral regimens. Moderate-to-severe elevations in serum aminotransferase levels (>5 times the upper limit of normal) are found in 3% to 10% of patients, although rates may be higher in patients with HIV-HCV coinfection. These elevations are usually asymptomatic and self-limited and can resolve even with continuation of the medication. Clinically apparent liver disease due to lopinavir/ritonavir occurs, but is rare. The latency to onset of symptoms or jaundice is usually 1 to 8 weeks and the pattern of serum enzyme elevations varies from hepatocellular to cholestatic or mixed. The injury is usually self-limited; however, fatal cases have been reported. In addition, initiation of lopinavir/ritonavir based highly active antiretroviral therapy can lead to exacerbation of an underlying chronic hepatitis B or C in coinfected individuals, typically arising 2 to 12 months after starting therapy, and associated with a hepatocellular pattern of serum enzyme elevations and increases in serum levels of hepatitis B virus (HBV) DNA or hepatitis C virus (HCV) RNA. Lopinavir therapy has not been clearly linked to lactic acidosis and acute fatty liver that is reported in association with several nucleoside analogue reverse transcriptase inhibitors.

来源:LiverTox

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（增加抗心律失常药的血浆浓度）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额外监测。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）和清蛋白均有结合，但与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毫克克立芝每日两次的浓度范围内保持恒定，并且在健康志愿者与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

在一项HIV-1阳性受试者（n=19）的药代动力学研究中，连续3周每天两次与食物同服400/100毫克KALETRA的多剂量给药产生了平均±标准差洛匹那韦峰血浆浓度（Cmax）为9.8±3.7微克/毫升，大约在给药后4小时达到。早晨剂量前稳态谷浓度平均为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。与利托那韦共同配制的洛匹那韦在人体中的绝对生物利用度尚未确定。在非空腹条件（500千卡，25%来自脂肪）下，KALETRA共同配制的胶囊和口服溶液给药后的洛匹那韦浓度相似。在空腹条件下给药时，KALETRA口服溶液相对于胶囊制剂的洛匹那韦平均AUC和Cmax均降低了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。在食物伴随下，多次剂量为每日一次800/200 mg的Kaletra，持续4周（n = 24），产生了洛匹那韦平均峰血浆浓度（Cmax）为11.8 ± 3.7 ug/mL，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 ug/mL，给药间隔内的最低浓度为1.7 ± 3.7 1.6 ug/mL。24小时给药间隔内洛匹那韦的AUC平均为154.1 ± 3.7 61.4 ug* h/mL。

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

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

• Crystalline pharmaceutical
  申请人：——

  公开号：US20010051721A1

  公开（公告）日：2001-12-13

  New crystalline forms of lopinavir are disclosed.

  揭示了洛匹那韦的新晶体形式。
• Methods for preparing stabilized amorphous drug formulations using acoustic fusion
  申请人：Merck Sharp & Dohme Corp.

  公开号：US11344496B2

  公开（公告）日：2022-05-31

  The present invention relates to methods for producing a stable amorphous dispersion of a pharmaceutically active substance having poor water solubility by applying low frequency acoustic energy to a mixture comprising the active substance and at least one polymer and heating the mixture until a stable amorphous dispersion is formed. The methods of the invention are an effective means of converting a crystalline API to a substantially amorphous and stable form, i.e., wherein the crystallinity is less than about 5%. The methods of the invention result in more complete amorphization, increased solubility, drug loading and stability as compared typical amorphization or literature methods.

  本发明涉及通过对包含活性物质和至少一种聚合物的混合物施加低频声能并加热该混合物直至形成稳定的无定形分散体，生产水溶性差的药物活性物质的稳定无定形分散体的方法。本发明的方法是将结晶性原料药转化为基本无定形的稳定形式（即结晶度小于约 5%）的有效方法。与典型的非晶化或文献方法相比，本发明的方法可使非晶化更彻底，溶解度、药物载量和稳定性更高。
• CRYSTALLINE PHARMACEUTICAL
  申请人：Abbott Laboratories

  公开号：EP1268442A2

  公开（公告）日：2003-01-02
• DOSAGE FORM COMPRISING NON-CRYSTALLINE LOPINAVIR AND CRYSTALLINE RITONAVIR
  申请人：ratiopharm GmbH

  公开号：EP2822553B1

  公开（公告）日：2016-05-18
• Crystalline Pharmaceutical
  申请人：Dickman Daniel A.

  公开号：US20110281900A1

  公开（公告）日：2011-11-17

  New crystalline forms of lopinavir are disclosed.