[(1S,4S,5S,6R,9S,10R,14R)-5,6-dihydroxy-7-(hydroxymethyl)-3,11,11,14-tetramethyl-15-oxo-4-tetracyclo[7.5.1.01,5.010,12]pentadeca-2,7-dienyl] (Z)-2-methylbut-2-enoate

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: [(1S,4S,5S,6R,9S,10R,14R)-5,6-dihydroxy-7-(hydroxymethyl)-3,11,11,14-tetramethyl-15-oxo-4-tetracyclo[7.5.1.01,5.010,12]pentadeca-2,7-dienyl] (Z)-2-methylbut-2-enoate
• 化学式: C₂₅H₃₄O₆
• 分子量: 430.5
• InChiKey: VDJHFHXMUKFKET-XCHJBCONSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  104
• 氢给体数：
  3
• 氢受体数：
  6

ADMET

代谢

ingenol mebutate在体外在大鼠、狗、小型猪和人类的血液、皮肤匀浆和肝细胞中的代谢特性基本相似。发现ingenol mebutate在血液和皮肤匀浆中相对稳定，并在冷冻保存的肝细胞中发生广泛代谢。在大鼠、狗和小型猪的肝细胞中，主要途径是水解为ingenol，而在人类中，主要途径是对ingenol mebutate进行羟基化。在大鼠、狗、小型猪和人类的皮肤中，ingenol mebutate的主要重排产物是PEP015（约占26%至31%）和PEP025（约占1%至2%）；水解为ingenol的情况很少（0%至0.81%）。然而，在大鼠和小型猪经皮或静脉注射ingenol mebutate后，未检测到PEP025，PEP015的浓度低于相应ingenol mebutate浓度的10%。

The in vitro metabolism of ingenol mebutate was qualitatively similar in blood, skin homogenates and hepatocytes of rats, dogs, minipigs and humans. Ingenol mebutate was found to be relatively stable in blood and skin homogenates, and to undergo extensive metabolism in cryopreserved hepatocytes. The major pathway in rat, dog and minipig hepatocytes was hydrolysis to ingenol, whereas the major pathway in humans was hydroxylation of ingenol mebutate. In the skin of rats, dogs, minipigs and humans, rearrangement of ingenol mebutate was predominantly to PEP015 (approximately 26% to approximately 31%) and, to a much lesser extent, PEP025 (approximately 1% to approximately 2%); hydrolysis to ingenol was minimal (0% to 0.81%). However, after topical or IV administration of ingenol mebutate to rats and minipigs, PEP025 was not detected and PEP015 was less than 10% of the corresponding ingenol mebutate concentration in the blood.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用： ingenol mebutate是一种白色至淡黄色结晶性粉末。作为药物Picato，它被用作凝胶，用于局部治疗光化性角化病。人类暴露和毒性：三项健康志愿者药理学研究的结果表明，ingenol mebutate凝胶的局部安全性较好，没有观察到皮肤致敏、光照射或光过敏性。然而，局部过量可能会导致局部皮肤反应的发生率增加。动物研究：在大鼠连续静脉注射28天的研究中，与治疗相关的影响包括短暂的呼吸急促（与剂量无关）、乏力/行为抑制以及食物摄入量减少。在小鼠连续给药7天的研究中，接受60微克/千克/天的动物中有一只，以及接受>/= 80微克/千克/天的所有动物，在给药</= 4天后因体症严重而被提前处死，这些体症与剂量有关。在小型猪中，5微克/千克/天连续4天或3微克/千克/天连续28天的ingenol mebutate没有导致死亡。与治疗相关的影响仅限于在2.5微克/千克/天偶尔出现且短暂的抑制行为、呕吐以及体重增长略微减少。在静脉注射ingenol mebutate的怀孕兔子中，观察到胚胎胎儿死亡率以及胎儿内脏和骨骼变异的发生率增加。在怀孕大鼠静脉注射后，没有观察到对胚胎胎儿毒性或致畸性的影响。在体外Ames试验、小鼠淋巴瘤试验和体内大鼠微核试验中，ingenol mebutate未表现出致突变性。体外叙利亚仓鼠胚胎（SHE）细胞转化试验为阳性。在一项对154只大鼠进行的6个月重复静脉注射研究中，发现有一只雄性和一只雌性大鼠每周两次以15微克/千克的剂量给药，出现了肾脏小管腺瘤和肾脏小管增生。具有肾脏腺瘤的雌性大鼠还出现了垂体腺瘤。在1个月的恢复期宰杀时，有一只雄性大鼠出现了甲状腺滤泡细胞癌。

IDENTIFICATION AND USE: Ingenol mebutate is a white to pale yellow crystalline powder. As the drug Picato, it is used as a gel for the topical treatment of actinic keratosis. HUMAN EXPOSURE AND TOXICITY: Results from three pharmacology studies in healthy volunteers indicate a favorable topical safety profile for ingenol mebutate gel, with no evidence seen of skin sensitization, photoirradiation, or photoallergic potential. However, topical overdosing could result in an increased incidence of local skin reactions. ANIMAL STUDIES: In rats given repeat IV dosing for 28 days, treatment-related effects included transient tachypnea, which was not dose-related, lethargy and/or subdued behavior and decreased food consumption. In mice dosed for 7 consecutive days, one animal receiving 60 ug/kg/day and all animals receiving >/= 80 ug/kg/day were killed prematurely after </= 4 days of dosing because of the severity of physical signs, which were dose-related. In mini-pigs, no deaths occurred at 5 ug/kg/day ingenol mebutate for 4 consecutive days or 3 ug/kg/day for 28 days. Treatment-related effects were limited to sporadic and transient subdued behavior, emesis and slightly reduced body weight gain post-dose at 2.5 ug/kg/day. An increase in embryo-fetal mortality as well as increased incidence of fetal visceral and skeletal variations was noted in pregnant rabbits exposed to ingenol mebutate intravenously. No treatment related effects on embryofetal toxicity or teratogenicity were noted after intravenous administration to pregnant rats. Ingenol mebutate was not mutagenic in an in vitro Ames test, mouse lymphoma assay, and in vivo rat micronucleus test. An in vitro Syrian hamster embryonic (SHE) cell transformation assay was positive. A 6-month repeat dose IV rat study in 154 rats found that one male and one female dosed twice weekly with 15 ug/kg had a kidney tubular adenoma and tubular hyperplasia of the kidney. A pituitary adenoma was also present in the female with the renal adenoma. At the 1-month recovery kill, one male had a thyroid follicular cell carcinoma.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中毒物清除。如果患者停止呼吸，开始人工呼吸，最好使用需求阀复苏器、袋阀面罩装置或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐，让患者前倾或置于左侧（如果可能的话，头部向下），以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，协助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预期癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能够吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β受体激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W维持开放/"To keep open"，最低流速/。如果出现低血容量的迹象，使用0.9%的生理盐水（NS）或乳酸钠林格氏液（LR）。对于伴有低血容量迹象的低血压，谨慎给予液体。注意观察液体过载的迹象……。用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/毒物A和B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

/HUMAN EXPOSURE STUDIES/ 健康志愿者被纳入单中心、随机、对照、同一受试者比较试验中。PEP005-005被设计为重复刺激贴片试验。在PEP005-023中，照射后检查治疗区域以评估光刺激性潜力；评估皮肤反应。在PEP005-024中，进行照射以确定药物的光过敏性（光敏作用）潜力。所有治疗区域在照射前和照射后24、48和72小时进行分级。在所有研究中，使用序数评分系统在药物应用/照射前后设定的时间间隔内视觉评估局部耐受性。在PEP005-005（n=238）中， ingenol mebutate与载体的平均和总累积刺激评分之间存在显著差异（p<0.001）。在PEP005-023（n=34）中，所有照射的治疗区域出现轻度红斑，这与紫外线剂量预期相符。无论是否照射，对ingenol mebutate或载体的临床显著刺激反应均无出现。在PEP005-024（n=60）中，照射的治疗区域对ingenol mebutate或载体的刺激反应无显著差异。三项健康志愿者的药理学研究结果表明，ingenol mebutate凝胶具有有利的局部安全性特征，没有出现皮肤致敏、光刺激或光过敏性潜力的证据。

/HUMAN EXPOSURE STUDIES/ Healthy volunteers were enrolled in single-center, randomized, controlled, within-subject comparison trials. PEP005-005 was designed as a repeat-insult patch test study. In PEP005-023, treatment areas were examined after irradiation for photoirritation potential; dermal reactions were evaluated. In PEP005-024, irradiation was performed to determine the photoallergic (photosensitizing) potential of the medication. All treatment areas were graded immediately prior to irradiation and 24, 48, and 72 hours following irradiation. In all studies, local tolerability was assessed visually using an ordinal scoring system at set intervals before and after medication application/irradiation. In PEP005-005 (n=238), a significant difference (p<0.001) was seen between ingenol mebutate and vehicle for mean and total cumulative irritation scores. In PEP005-023 (n=34), mild erythema in all irradiated treatment areas was as expected for the ultraviolet dose. There was no clinically significant irritation in response to ingenol mebutate or vehicle, irrespective of irradiation. In PEP005-024 (n=60), there was no significant irritation in response to either ingenol mebutate or vehicle at their irradiated treatment areas. Results from three pharmacology studies in healthy volunteers indicate a favorable topical safety profile for ingenol mebutate gel, with no evidence seen of skin sensitization, photoirritation, or photoallergic potential.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

使用简单的异速增长相关性估算人体的血浆清除率和分布容积（稳态），基于体重。采用一室模型，一级吸收和消除动力学，估算出以2微克/千克/天的最大意向临床剂量进行皮肤给药，会在血液中产生低于0.1纳克/毫升的LLOQ的 ingenol mebutate 水平。稳态下的血液清除率和分布容积预计分别在约0.22至1.01升/小时/千克和约0.61升/千克之间。吸收速率常数和局部生物利用度预计分别为0.0277小时^-1和0.21%。对于2微克/千克/天的局部剂量，预计人体的血液Tmax为2小时，Cmax为0.107皮克/毫升。为了产生可检测的血液水平，人类至少需要2000微克/千克/天的局部剂量。

Plasma clearance and volume of distribution (steady-state) in humans were estimated using a simple allometric correlation based on body weight. Using a one-compartment model with first-order absorption and elimination kinetics, it was estimated that dermal administration of the maximum intended clinical dose of 2 ug/kg/day would produce levels of ingenol mebutate in the blood below the LLOQ of 0.1 ng/mL. Blood clearance and volume of distribution at steady-state were predicted to range from approximately 0.22 to 1.01 L/hr/kg and approximately 0.61 L/kg, respectively. The absorption rate constant and topical bioavailability was projected to be 0.0277 hours-1 and 0.21%, respectively. A human blood Tmax of 2 hours and Cmax of 0.107 pg/mL were predicted for a 2 ug/kg/day topical dose. A minimum topical dose of 2000 ug/kg/day to humans would be required produce detectable blood levels.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉给药后，在大鼠、家兔、狗和小型猪中观察到了高至非常高的血液清除率、稳态时中等到高分布体积和短半衰期。大鼠静脉注射3(H)-ingenol甲酸后，与药物相关的放射性物质在组织中分布良好，接触器官没有性别差异，但雌性大鼠的消除速度更快。在体外实验中，ingenol甲酸及其同分异构体在大鼠、狗、小型猪和人类中显示出高血浆蛋白结合率(>99%)。在大鼠中，静脉注射的3(H)-ingenol甲酸大部分通过胆汁途径排泄，尿液排泄为次要途径。

After IV administration, a high to very high blood clearance, moderate to high volume of distribution at steady-state and short half-life were observed in rats, rabbits, dogs and minipigs. Following IV administration of 3(H)-ingenol mebutate to rats, drug-related radioactivity was well distributed to the tissues and there were no gender differences in the organs exposed but elimination was faster in females. In vitro, ingenol mebutate and its isomers were shown to have high plasma protein binding in rats, dogs, minipigs and humans (>99%). In rats, the majority of an intravenous dose of 3(H)-ingenol mebutate was excreted via the biliary route, with urinary excretion as a minor pathway.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在体外将0.01%、0.1%或0.05% PEP005凝胶应用于大鼠、迷你猪和人体皮肤制剂后，经皮吸收通常较低，动物种类间的范围从0.04%（迷你猪）到8.68%（大鼠），在人体中为0.16%到1.93%。3(H)-ingenol甲酸酯的吸收剂量顺序为WI大鼠 > SD大鼠 > 人类 > 迷你猪。在将PEP005凝胶局部应用于迷你猪后，血液中的ingenol甲酸酯水平通常未被检测到，当检测到时，水平最高可达0.1 ng/mL。在大鼠局部应用ingenol甲酸酯后，只有在300 ug/kg或更高剂量时，血液水平才持续可量化，在这种情况下，绝对生物利用度为2%到4%。

After in vitro applications of 0.01%, 0.1% or 0.05% PEP005 Gels to rat, mini-pig and human skin preparations, the percutaneous absorption was generally low, with a range of 0.04% (mini-pig) to 8.68% (rat) across animal species and 0.16% to 1.93% in humans. The absorbed doses of 3(H)-ingenol mebutate were in the order of WI rat > SD rat > human > mini-pig. After topical administration of PEP005 Gel to mini-pigs, blood levels of ingenol mebutate were generally not detected, and when detected, ranged up to 0.1 ng/mL. After topical administration of ingenol mebutate to rats, blood levels were consistently quantifiable only at doses of 300 ug/kg or greater, in which case the absolute bioavailability was 2% to 4%.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Picato凝胶，0.05%的系统暴露在两项研究中对总共16名AK（光化性角化病）患者进行了评估，这些研究是在连续两天内，每天一次将大约1克Picato凝胶，0.05%应用于100平方厘米的背部前臂区域后进行的。在这些研究中，测量了 ingenol mebutate（英格诺尔甲酸）及其两种代谢物（ingenol mebutate的酰基异构体）的血药水平。受评估对象的血样中ingenol mebutate及其两种代谢物的水平均低于定量下限（0.1 ng/mL）。

The systemic exposure to Picato gel, 0.05% was assessed in two studies in a total of 16 subjects with AK, following application of approximately 1 g of Picato gel, 0.05% to an area of 100 cm2 of the dorsal forearm once daily for two consecutive days. In these studies, the blood levels of ingenol mebutate and two of its metabolites (acyl isomers of ingenol mebutate) were measured. Blood levels of ingenol mebutate and the two metabolites were below the lower limit of quantification (0.1 ng/mL) in all the blood samples of the subjects evaluated.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为产物：
  描述：

  以71的产率得到[(1S,4S,5S,6R,9S,10R,14R)-5,6-dihydroxy-7-(hydroxymethyl)-3,11,11,14-tetramethyl-15-oxo-4-tetracyclo[7.5.1.01,5.010,12]pentadeca-2,7-dienyl] (Z)-2-methylbut-2-enoate
  参考文献：
  名称：

  Bioorg. Med. Chem. Lett. 2013, 23, 5624-5629

  摘要：

  DOI：

文献信息

• [EN] METHODS OF SYNTHESIS OF INGENOL AND INTERMEDIATES THEREOF<br/>[FR] PROCÉDÉS DE SYNTHÈSE D'INGÉNOL ET DE SES INTERMÉDIAIRES
  申请人：LEO LAB LTD

  公开号：WO2014191457A1

  公开（公告）日：2014-12-04

  The present invention relates generally to methods of synthesis of diterpene heterocylic compounds. More particularly, the present invention relates to efficient methods of synthesis of ingenol (Formula (21), CAS 30220-46-3), from a compound of formula (1). The present invention also provides for various advantageous intermediates along the synthetic route of ingenol. Efficient synthesis of ingenol is important in the design and synthesis of related analogues, such as ingenol-3-angelate.

  本发明涉及合成二萜杂环化合物的方法。更具体地说，本发明涉及从公式（1）的化合物中高效合成英吉利醇（式（21），CAS 30220-46-3）的方法。本发明还提供了在合成英吉利醇的合成路线中各种有利的中间体。高效合成英吉利醇对于设计和合成相关类似物，如英吉利醇-3-安格酸酯，是非常重要的。
• [EN] A METHOD OF PRODUCING INGENOL-3-ANGELATE<br/>[FR] PROCÉDÉ DE PRODUCTION D'INGÉNOL-3-ANGÉLATE
  申请人：LEO PHARMA AS

  公开号：WO2012010172A1

  公开（公告）日：2012-01-26

  The present invention relates to methods of producing ingenol-3-angelate (I) from ingenol (II). Formula (I) and (II). Furthermore, the invention relates to intermediates useful for the synthesis of ingenol-3-angelate (I) from ingenol (II) and to methods of producing said intermediates.

  本发明涉及从英吉利醇(II)制备英吉利醇-3-丁酯(I)的方法。公式(I)和(II)。此外，本发明涉及用于从英吉利醇(II)合成英吉利醇-3-丁酯(I)的中间体以及制备所述中间体的方法。
• Bioorg. Med. Chem. Lett. 2013, 23, 5624-5629
  作者：

  DOI：——

  日期：——
• Synlett. 2012, 23, 2647-2652
  作者：

  DOI：——

  日期：——
• METHODS OF SYNTHESIS OF INGENOL AND INTERMEDIATES THEREOF
  申请人：Leo Laboratories Limited

  公开号：EP3004036B1

  公开（公告）日：2017-11-22