喷他脒 | 100-33-4

• 物质功能分类: 原料药 - 抗寄生虫病药 - 抗丝虫病及抗利什曼原虫病药
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 中文名称: 喷他脒
• 中文别名: 4,4'-二脒基二苯氧基戊烷；4,4"-二脒基二苯氧基戊烷
• 英文名称: pentamidine
• 英文别名: 4-[5-(4-carbamimidoylphenoxy)pentoxy]benzenecarboximidamide
• CAS: 100-33-4
• 化学式: C₁₉H₂₄N₄O₂
• 分子量: 340.425
• InChiKey: XDRYMKDFEDOLFX-UHFFFAOYSA-N

物化性质

• 熔点：
  186 °C (dec.)
• 沸点：
  476.22°C (rough estimate)
• 密度：
  1.1805 (rough estimate)
• 溶解度：
  可溶于DMSO、甲醇（少量）
• 物理描述：
  Solid
• 颜色/状态：
  Crystallizes as colorless plates from water
• 蒸汽压力：
  1.66X10-10 mm Hg at 25 °C (est)
• 稳定性/保质期：
  After reconstitution with sterile water, the Pentam solution is stable for 48 hours in the original vial at room temperature if protected from light.

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  25
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  118
• 氢给体数：
  4
• 氢受体数：
  4

ADMET

代谢

肝脏的。

Hepatic.

来源:DrugBank

代谢

通过使用高效液相色谱，研究了在大鼠肝脏匀浆离心（9,000 x g）上清液中戊眯（pentamidine）转化为相应脒氧亚胺（N-羟基戊眯和N,N'-二羟基戊眯）的体外转化。通过液态二次离子质谱和疑似代谢物的一清二楚的合成，确认了色谱图中两个脒氧亚胺峰的存在。发现这些代谢反应是由细胞色素P-450系统（混合功能氧化酶）催化的。单羟基化产物的形成具有0.48 mM的Km和每毫克蛋白质29.50 pmol/min的Vmax，而二羟基化代谢物具有0.73 mM的Km和每毫克蛋白质4.10 pmol/min的Vmax。

By using high-performance liquid chromatography, the in vitro conversion of pentamidine to the corresponding amidoximes (N-hydroxypentamidine and N,N'-dihydroxypentamidine) was studied in supernatants of rat liver homogenate centrifuged at 9,000 x g. The presence of the two amidoxime peaks in chromatograms was confirmed by liquid secondary ion mass spectrometry and by unequivocal synthesis of the suspected metabolites. The metabolic reactions were found to be catalyzed by the cytochrome P-450 system (mixed-function oxidases). The formation of the monohydroxylated product was found to have a Km of 0.48 mM and a Vmax of 29.50 pmol/min per mg of protein, while the dihydroxylated metabolite had a Km of 0.73 mM and a Vmax of 4.10 pmol/min per mg of protein. ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

抗原虫/抗真菌药物戊脒[1,5-双(4-脒基苯氧基)戊烷]最近被显示可以通过大鼠肝部分转化为至少六种可能的代谢物，这是通过高效液相色谱检测到的。在这项研究中，两种主要的微粒体代谢物被识别为戊脒的2-戊醇和3-戊醇类似物[1,5-双(4-脒基苯氧基)-2-戊醇；和1,5-双(4-脒基苯氧基)-3-戊醇]。此外，第七种可能的代谢物被发现并识别为对羟基苯甲脒，这是原始药物的片段。已经证明细胞色素P-450是负责戊脒代谢的酶系统……混合功能氧化酶容易将戊脒转化为羟基化代谢物，但具体哪个（些）细胞色素P-450同种物负责这一点还不清楚。

The antiprotozoal/antifungal drug pentamidine [1,5-bis(4-amidinophenoxy)pentane] has been recently shown to be metabolized by rat liver fractions to at least six putative metabolites as detected by high-performance liquid chromatography. ... In this study, the two major microsomal metabolites have been identified as the 2-pentanol and 3-pentanol analogs of pentamidine [1,5-di(4-amidinophenoxy)-2-pentanol; and 1,5-bis(4-amidinophenoxy)-3-pentanol]. As well, a seventh putative metabolite has been discovered and identified as para-hydroxybenzamidine, a fragment of the original drug. ... the cytochromes P-450 have been demonstrated as the enzyme system responsible for pentamidine metabolism ... the mixed-function oxidases readily convert pentamidine to hydroxylated metabolites, but exactly which isozyme(s) of cytochrome P-450 is responsible is not clear.

来源:Hazardous Substances Data Bank (HSDB)

代谢

抗原生动物药物戊脒[1,5-双(4'-脒基苯氧基)戊烷]之前已被证明可以通过大鼠肝微粒体进行代谢，并且已经鉴定出七种假定主要代谢物中的五种。随着5-(4'-脒基苯氧基)戊酸和5-(4'-脒基苯氧基)-1-戊醇作为剩余两种代谢物的合成和鉴定，戊脒在大鼠中的初级代谢似乎已经完全表征。... 使用[14C]戊脒和孤立、灌注的大鼠肝脏来识别次级代谢物。通过高效液相色谱法分析灌注肝脏样本，仅检测到两个新的放射性峰。用硫酸酯酶或β-葡萄糖醛酸酶处理肝脏样本，导致这些峰的降低或消除，并产生了被鉴定为对羟基苯脒和5-(4'-脒基苯氧基)戊酸的峰。根据这些结果，得出结论只有这两种初级代谢物与硫酸或葡萄糖醛酸结合。

The antiprotozoal drug pentamidine [1,5-bis(4'-amidinophenoxy)pentane] has been previously shown to be metabolized by rat liver microsomes, and five of the seven putative primary metabolites have been identified. With the synthesis and identification of 5-(4'-amidinophenoxy)pentanoic acid and 5-(4'-amidinophenoxy)-1-pentanol as the remaining two metabolites, the primary metabolism of pentamidine in rats appears fully characterized. ... Isolated, perfused rat livers were used with [14C]pentamidine to identify secondary metabolites. Only two novel radioactive peaks were detected by HPLC analysis of perfused liver samples. The treatment of liver samples with sulfatase or beta-glucuronidase resulted in the reduction or elimination of these peaks and gave rise to peaks identified as para-hydroxybenzamidine and 5-(4'-amidinophenoxy)pentanoic acid. It was concluded from these results that only these two primary metabolites were conjugated with sulfate or glucuronic acid.

来源:Hazardous Substances Data Bank (HSDB)

代谢

戊眯定是人肝脏微粒体P450酶CYP2C19的底物。/从表中/

Pentamidine /is a substrate for/ human liver microsomal P450 enzyme CYP2C19. /From table/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

戊烷脒的作用机制尚未完全了解。据认为，该药物干扰核代谢，从而抑制DNA、RNA、磷脂和蛋白质的合成。

The mode of action of pentamidine is not fully understood. It is thought that the drug interferes with nuclear metabolism producing inhibition of the synthesis of DNA, RNA, phospholipids, and proteins.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

喷他脒与接受2到3周治疗的肺孢子菌肺炎患者的血清转氨酶升高有关，患病率为9%至15%。临床明显的肝损伤在使用过程中也有报道，但总是与多种其他严重并发症有关，如呼吸或肾功能衰竭和胰腺炎。损伤的出现通常在开始治疗后的几天内，特点是急性肝坏死，血清转氨酶水平显著升高，凝血酶原时间延长迅速发展，且胆汁最少或没有。恢复通常是迅速的，通常是完全的。

Pentamidine has been associated with serum aminotransferase elevations in 9% to 15% of patients receiving 2 to 3 weeks of therapy for pneumocystis pneumonia. Clinically apparent liver injury has also been reported with its use, but always in association with multiple other severe complications, such as respiratory or renal failure and pancreatitis. The onset of injury is within days of starting therapy and is characterized by acute hepatic necrosis, marked elevations in serum aminotransferase levels, rapid development of prolongation of prothrombin time and minimal or no jaundice. Recovery is typically rapid and usually complete.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：戊脒

Compound:pentamidine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：低药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

通过胃肠道的吸收不良，通常通过非胃肠道途径给药。

Absorbed poorly through the gastrointestinal tract and is usually administered parenterally.

来源:DrugBank

吸收、分配和排泄

戊烷脒乳酸钠通过注射部位给药能够较好地被吸收，尽管可能会在使用后形成无菌性脓肿。单次静脉给药后，药物从血浆中消失，表观半衰期为几分钟到几小时；之后是一个较慢的分布相和一个持续数周到数月的长期消除相。非洲锥虫病患者在药代动力学参数上表现出明显的个体间差异。单次给药后，他们的平均系统血浆清除率约为1120毫升/分钟，但分布体积约为25000升，这一发现解释了平均消除半衰期约为12天的长时间。戊烷脒的肾清除率平均仅为全身清除率的2%到11%……但药物是否被代谢或通过胆汁排泄……尚不清楚。在接受为期13天的多剂次注射治疗肺囊虫病的患者中，药物会累积，以至于无法达到稳态血浆浓度……/戊烷脒乳酸钠/

Pentamidine isethionate is fairly well absorbed from parenteral sites of admin despite the formation of sterile abscesses that may occur after its used. Following a single intravenous dose, the drug disappears from plasma with an apparent half-life of several min to a few hours; this is followed by a slower distribution phase and a prolonged elimination phase lasting from weeks to months. Patients with African trypanosomiasis exhibit marked interindividual variations in pharmacokinetic parameters. Their mean system plasma clearance after a single dose is about 1120 mL/min, but the volume of distribution is about 25,000 L, a finding that accounts for the prolonged average elimination half-life of about 12 days ... The renal clearance of pentamidine averages only about 2% to 11% of its systemic clearance ... but whether the drug is metabolized or excreted in bile ... is unknown. In patients receiving multiple injections of the drug over a 13-day period for treatment of pneumocystosis, drug accumulation occurs such that no steady-state plasma concn is attained ... /Pentamidine isethionate/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在多次静脉注射后，艾滋病患者肝脏、肾脏、肾上腺和脾脏中的药物浓度最高，而在大脑中仅发现微量。此类患者的肺部在每日5次剂量为4毫克/公斤的药物后，含有中等的但具有治疗作用的浓度。为了预防或作为轻度到中度卡氏肺囊虫肺炎的辅助治疗，应该通过吸入戊烷脒气溶胶来达到更高的肺部浓度；与静脉给药相比，通过此途径给药导致较少的系统吸收和降低的毒性，适用于成人和儿童。实际递送到肺部的剂量取决于雾化器产生的颗粒大小和患者的通气模式。/戊烷脒乳酸盐/

... After multiple parenteral doses, the liver, kidney, adrenal, and spleen of patients with AIDS contain the highest concn of drug, whereas only traces are found in the brain ... Lungs of such patients contain intermediate but therapeutic concn after 5 daily doses of 4 mg of base/kg. Higher pulmonary concn should be achieved by inhalation of pentamidine aerosols for prophylaxis or as adjunctive treatment for mild to moderate Pneumocystis carinii pneumonia; delivery of drug by this route results in little systemic absorption and decreased toxicity compared with intravenous admin in both adults and children. The actual dose delivered to the lungs depends on both the size of particles generated by the nebulizer and the patient's ventilatory patterns. /Pentamidine isethionate/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

气溶胶化的戊脒定在肺部的浓度大约是静脉注射戊脒定的10到100倍。

Aerosolized pentamidine produces concentrations approximately 10 to 100 times higher in the lungs than would a comparable dose of IV pentamidine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

系统对吸入的五价联胺的吸收是微量的，在大多数情况下，经过4 mg/kg的雾化剂量后，血清中的五价联胺浓度小于20纳克/毫升（与单次静脉注射4 mg/kg后的612纳克/毫升相比）。系统吸收的高峰出现在吸入治疗完成时或接近完成时。

Systemic absorption of inhaled pentamidine is minimal, with serum pentamidine concentrations less than 20 nanograms per mL after a nebulized dose of 4 mg/kg in most cases (versus 612 nanogram per mL after a single IV dose of 4 mg/kg). Peak systemic absorption occurs at, or near, completion of inhalation therapy.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(b)
• 危险品运输编号：
  UN 3249
• RTECS号：
  CV6475000
• 海关编码：
  2925290090
• 包装等级：
  III
• 危险类别：
  6.1(b)
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  -20°C 冰箱，在惰性气氛下

制备方法与用途

生物活性

Pentamidine (MP-601205) 是一种抗微生物剂，能够干扰 DNA 的生物合成。它能抑制寄生虫 Leishmania infantum，IC50 为 2.5 μM，并且是有效的选择性蛋白酪氨酸磷酸酶 (PTPases) 和再生肝磷酸酶 (PRL) 抑制剂。Pentamidine 还可用于研究冈比亚锥虫病、抗锑利什曼病和卡氏肺孢子虫肺炎，具有抗肿瘤活性和抗菌活性。

靶点

• IC50: 2.5 μM（Leishmania infantum）
• 蛋白酪氨酸磷酸酶 (PTPases)
• 再生肝磷酸酶 (PRL)

体外研究

Pentamidine 在浓度依赖性地抑制 WM9、DU145、C4-2、Hey、WM480 和 A549 细胞的生长。与顺铂相比，Pentamidine 碘酸盐对利什曼原虫寄生体 Leishmania infantum 的杀灭活性高 60 倍，并且诱导程序性细胞死亡 (PCD) 比顺铂更多，这与 DNA 合成的抑制和 G2/M 期细胞周期停滞有关。Pentamidine 碘酸盐与胎牛胸腺 DNA 结合导致双螺旋结构发生构象变化，符合 B→A 转化。Pentamidine 碘酸盐与泛素结合使蛋白质 β-片层含量增加了 6%。

细胞活力测定

细胞系	浓度 (µg/mL)	培养时间 (天)	结果
WM9, DU145, C4-2, Hey, WM480, A549	0-10	6	所有六个细胞系的生长浓度依赖性地受到抑制，在 10 µg/mL 浓度下完全抑制了所有细胞系的生长。

体内研究

Pentamidine (0.25 mg/鼠；肌内注射；每两天一次；共4周) 显著抑制裸鼠 WM9 人黑色素瘤肿瘤的生长。

动物模型

| 动物模型 | 细胞系 | 剂量 (mg/鼠) | 管理方式 | 时间（天） | 结果 | |------------------------------|-----------|----------------|-----------------|-------------| | 裸鼠 (6 周龄)，注射 WM9 细胞 | WM9 | 0.25 | 肌内注射；每两天一次；共4周 | | 显著抑制裸鼠 WM9 人黑色素瘤肿瘤的生长。 |

反应信息

• 作为反应物：
  描述：

  喷他脒 、 4,8,13,17,21-五甲基-4,8,12,16,20-二十二碳五烯酸 以 乙醇 、 水 为溶剂， 反应 0.25h， 生成
  参考文献：
  名称：

  Selective delivery of pentamidine toward cancer cells by self-assembled nanoparticles

  摘要：

  DOI：

  10.1016/j.ijpharm.2022.122102
• 作为产物：
  描述：

  1,5-二溴戊烷 在 盐酸 、 氨 、 sodium ethanolate 作用下， 以 苯 为溶剂， 反应 126.0h， 生成 喷他脒
  参考文献：
  名称：

  Analogs of 1,5-bis(4-amidinophenoxy)pentane (pentamidine) in the treatment of experimental Pneumocystis carinii pneumonia

  摘要：

  A series of 33 analogues of the anti-Pneumocystis carinii drug 1,5-bis(4-amidinophenoxy)pentane (pentamidine) was synthesized for screening against a rat model of P. carinii pneumonia (PCP). Twenty-five of the compounds showed efficacy against PCP when compared to a saline-treated control group. Two compounds, 1,4-bis(4-amidinophenoxy)butane (butamidine, 6) and 1,3-bis(4-amidino-2-methoxyphenoxy)propane (DAMP, 16), were statistically more effective than the parent drug in treating PCP in the rat model of infection. In addition to their activity against PCP, the compounds were also evaluated for antitrypsin activity, ability to inhibit thymidylate synthetase, affinity for DNA, and toxicity. No correlation was observed between the tested molecular interactions of the diamidines and their effectiveness against PCP.

  DOI：

  10.1021/jm00166a026

文献信息

• Integrase inhibitors
  申请人：Cai R. Zhenhong

  公开号：US20080058315A1

  公开（公告）日：2008-03-06

  Tricyclic compounds, protected intermediates thereof, and methods for inhibition of HIV-integrase are disclosed.

  三环化合物，其受保护的中间体，以及用于抑制HIV整合酶的方法被披露。
• [EN] AZADECALIN DERIVATIVES AS INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS REPLICATION<br/>[FR] DÉRIVÉS D'AZADÉCALINE EN TANT QU'INHIBITEURS DE LA RÉPLICATION DU VIRUS DE L'IMMUNODÉFICIENCE HUMAINE
  申请人：VIIV HEALTHCARE UK (NO 5) LTD

  公开号：WO2018002848A1

  公开（公告）日：2018-01-04

  Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, azadecaline derivatives that possess unique antiviral activity are provided as HIV maturation inhibitors, as represented by compounds of Formula (I). These compounds are useful for the treatment of HIV and AIDS.

  具有药物和生物影响特性的化合物，其药物组合物和使用方法已列出。具体来说，提供了具有独特抗病毒活性的阿扎德卡林衍生物，作为HIV成熟抑制剂，如化合物(I)的公式所代表的那样。这些化合物对于治疗HIV和艾滋病是有用的。
• IRAK DEGRADERS AND USES THEREOF
  申请人：Kymera Therapeutics, Inc.

  公开号：US20190192668A1

  公开（公告）日：2019-06-27

  The present invention provides compounds, compositions thereof, and methods of using the same.

  本发明提供了化合物、其组合物以及使用这些化合物的方法。
• [EN] TRICYCLIC TRIAZOLE COMPOUNDS THAT MODULATE HSP90 ACTIVITY<br/>[FR] COMPOSÉS TRIAZOLES TRICYCLIQUES MODULANT L'ACTIVITÉ HSP90
  申请人：SYNTA PHARMACEUTICALS CORP

  公开号：WO2009139916A1

  公开（公告）日：2009-11-19

  The present invention relates to substituted tricyclic triazole compounds and compositions comprising substituted tricyclic triazole compounds. The invention further relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for preventing or treating hyperproliferative disorders, such as cancer, in a subject in need thereof comprising administering to the subject a compound of the invention, or a composition comprising such a compound.

  本发明涉及替代三环三唑化合物和包含替代三环三唑化合物的组合物。该发明还涉及在需要的受体中抑制Hsp90活性的方法，以及预防或治疗高增殖性疾病（如癌症）的方法，其中包括向受体施用本发明的化合物或包含这种化合物的组合物。
• Heterocyclic Compounds as MEK Inhibitors
  申请人：Chikkanna Dinesh

  公开号：US20090275606A1

  公开（公告）日：2009-11-05

  The present invention relates to compounds of formula I and pharmaceutically acceptable salts. These compounds can act as potential MEK inhibitors in the treatment of hyperproliferative diseases, like cancer and inflammation. The present invention also reveals methods of preparation thereof.

  本发明涉及公式I的化合物和药用盐。这些化合物可以作为潜在的MEK抑制剂，用于治疗癌症和炎症等过度增殖性疾病。本发明还揭示了其制备方法。