吡美莫司 | 137071-32-0

• 物质功能分类: 生物化工 - 抑制剂 - 免疫抑制剂
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯内酰胺
• 中文名称: 吡美莫司
• 中文别名: 匹美克莫司；33-表氯-33-脱氧长川霉素；33-表氯-33-脱氧子囊霉素
• 英文名称: pimecrolimus
• 英文别名: elidel；(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(E)-1-[(1R,3R,4S)-4-chloro-3-methoxycyclohexyl]prop-1-en-2-yl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone
• CAS: 137071-32-0
• 化学式: C₄₃H₆₈ClNO₁₁
• 分子量: 810.466
• InChiKey: KASDHRXLYQOAKZ-XDSKOBMDSA-N

物化性质

• 熔点：
  135-136 °C
• 沸点：
  866.1±75.0 °C(Predicted)
• 密度：
  1.19
• 溶解度：
  DMSO（微溶，超声处理）、氯仿（微溶）、甲醇（微溶）

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  56
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  158
• 氢给体数：
  2
• 氢受体数：
  11

ADMET

代谢

体外实验中未观察到人体皮肤对药物的代谢。口服给药后产生了来自O-脱甲基和氧化反应的代谢物。

No drug metabolism was observed in human skin in vitro. Oral administration yielded metabolites produced from O-demethylation and oxygenation reactions.

来源:DrugBank

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：外用他克莫司尚未在哺乳期进行过研究；然而，它已用于3个月大的儿童。因为它局部应用后吸收不良，且成年人的血浆浓度低于2 mcg/L，对哺乳婴儿的风险较低。确保婴儿的皮肤不直接接触涂抹过药物的皮肤区域。以前的建议指出，如果需要治疗乳房，首选其他药物；哺乳期间不要涂抹在乳头区域。最新的欧洲指南允许在哺乳后立即使用他克莫司，但在哺乳前需要轻轻仔细清洁乳头。只有水溶性乳膏或凝胶产品可以涂抹在乳房上，因为糊剂可能会使婴儿通过舔食接触到高水平的矿物石蜡。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关已发布信息。

◉ Summary of Use during Lactation:Topical pimecrolimus has not been studied during breastfeeding; however, it is used topically in children as young as 3 months of age. Because it is poorly absorbed after topical application and plasma concentrations after topical use in adults are less than 2 mcg/L, it is a low risk to the nursing infant. Ensure that the infant's skin does not come into direct contact with the areas of skin that have been treated. Older recommendations state that if the breast is to be treated, an alternate drug is preferred; do not apply to the nipple area while nursing. A newer European guideline allows pimecrolimus to be applied just after nursing, with the nipples cleaned gently and carefully before nursing. Only water-miscible cream or gel products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins via licking. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

74%-87%（体外，与血浆蛋白结合）

74%-87% (in vitro, bound to plasma proteins)

来源:DrugBank

吸收、分配和排泄

• 吸收

由于pimecrolimus在局部应用后的系统性吸收较低，无法可靠地计算出标准药代动力学参数，如AUC（药时曲线下面积）、Cmax（最大血药浓度）、半衰期等。

Because of the low systemic absorption of pimecrolimus following topical application the calculation of standard pharmacokinetic measures such as AUC, Cmax, half-life, etc. cannot be reliably done.

来源:DrugBank

吸收、分配和排泄

• 消除途径

80%的药物通过粪便排出。

80% of the drug is excreted in the feces.

来源:DrugBank

安全信息

• 危险品运输编号：
  NONH for all modes of transport

制备方法与用途

临床应用

美国FDA批准1%吡美莫司乳膏用于2岁以上无免疫抑制的轻度至中度特应性皮炎（AD）和湿疹患者，作为二线药物进行短期非持续治疗。德国特应性皮炎治疗指南建议，在不适合外用激素或预期长期治疗可能引起不可逆副作用的情况下，可选用钙调磷酸酶抑制剂如吡美莫司和他克莫司。对于敏感区域如面部、屈侧等部位，吡美莫司可作为一线药物使用，且耐受性优于糖皮质激素。

药代动力学

吡美莫司的药代动力学有两个显著特点：高亲脂性和大分子量。与他克莫司和糖皮质激素相比，吡美莫司具有更高的分布系数和更大的分子量（分别为6.99、810 uM、4.34-5.6和<500 uM）。体外研究显示，吡美莫司与皮肤蛋白的结合力约为他克莫司的三倍。由于其大分子量，吡美莫司难以穿透完整皮肤，大部分药物会积聚在表皮和真皮之间，进入血液循环的药量极少。

一项封包治疗特应性皮炎的研究表明，在晚上连续9天使用1%吡美莫司乳膏治疗中等至严重程度的患者后，84%患者的血药浓度低于0.5 ng/mL。另一项长期非封包研究也显示，2次/日治疗中等至严重的特应性皮炎6-12个月后，血药浓度范围为0.1~1.94 ng/mL，未发现药物蓄积现象。毒理学和药代动力学研究结果表明，外用吡美莫司超过30倍最大推荐人体用量并长期大面积使用，可能会导致淋巴组织增生性改变。

局部用免疫调节剂

吡美莫司是一种局部用免疫调节剂，由链霉菌产生的子囊素981（ASM 981）组成。它可特异性与胞质受体macrophilin-12结合，作为钙调蛋白抑制剂发挥作用。

在体外实验中，吡美莫司通过抑制磷酸酶功能阻断T淋巴细胞激活途径，并阻止细胞因子和促炎性介质从肥大细胞中释放。具体机制包括：形成pimecrolimus-macrophilin复合物并与其胞质酶钙调磷酸酶结合；通过抑制活化的T细胞中核因子的去磷酸化作用，阻断其激活过程；抑制Fc∈-RI介导的脱粒和分泌炎症性介质。此外，它还能降低与macrolactam靶点通路和炎症相关的基因mRNA表达。

体内研究

在小鼠体内，吡美莫司口服效果与环孢霉素A相当，皮下注射略逊于环孢霉素A。在过敏性接触皮炎模型中，与环孢霉素A和他克莫司相比，吡美莫司能持续抑制次级炎症反应而不损害初次免疫应答。在模拟急性过敏性皮炎信号的低镁无毛大鼠模型中，它有效降低了皮肤炎症和瘙痒。

此外，在局部移植物抗宿主反应、用绵羊红细胞形成抗体以及肾移植的大鼠体内实验中，与他克莫司相比，吡美莫司仅显示出较低电势以减弱全身免疫应答。在过敏性接触皮炎（ACD）猪模型和强效皮质类固醇氯倍他索-17-丙酸盐治疗效果相当。

反应信息

• 作为反应物：
  描述：

  甲醇 、 吡美莫司 以66%的产率得到
  参考文献：
  名称：

  氨基酸区域有修饰的新孢子霉素衍生物——5,6-脱氢孢子霉素的合成，生物活性和X射线晶体结构

  摘要：

  Abstractmagnified imageThe immunomodulatory macrolide ascomycin (1a) inhibits T‐cell activation via binding to macrophilin‐12 and inhibition of the phosphatase calcineurin. Its structural analogs pimecrolimus and tacrolimus have recently become available as the first novel topical treatments of atopic dermatitis since the introduction of topical corticosteroids in the 1950s. This stimulated the search for novel derivatives with an improved biological profile. Though several derivatives of 1a are known, only a few derivatives with modifications on the amino acid moiety are available because of the chemical inaccessibility of this region. To this end, we present here a new approach using a photochemical reaction as the key step. Thus, irradiation of ascomycin (1a) led to mixtures of the methoxy products 2a and 8, the cleavage product 4a, the but‐1‐enyl derivative 7, and the oxazolidinone 9 depending on the solvent. The selectivity of the reaction was improved to furnish 2a or 9 in preparatively useful yields. The mechanism and scope of the reaction were investigated. Starting from 2a, several analogs featuring novel modifications on the amino acid moiety, which are not easily accessible through routine methods, were synthesized in a few steps. Further, using the photoreaction key intermediates with potential for broader modifications on the amino acid moiety were synthesized, and their utility was exemplified by the synthesis of vinylpipecolic acid and vinylproline analogs. An interesting photochemical cleavage of the amide bond in the derivatives of ascomycin (1a) is presented. The structural and conformational features of the new analogs together with the X‐ray crystal structure of 5,6‐dehydroascomycin (6a) are presented, and their biological activities are discussed. Of all the derivatives, 6a showed the best activities in in vitro and in vivo models of allergic contact dermatitis whilst showing a lower risk of immunosuppression.

  DOI：

  10.1002/hlca.200800436
• 作为产物：
  描述：

  长川霉素 在 吡啶 、 三苯基二氯化膦 作用下， 以 乙腈 为溶剂， 反应 1.0h， 以32.4%的产率得到吡美莫司
  参考文献：
  名称：

  Heteroatoms-Containing Tricyclic Compounds

  摘要：

  一种从FR520一步制备33-Epi-33-chloro-FR 520的方法，其中避免使用保护基。

  公开号：

  US20080071082A1

文献信息

• [EN] PROCESS TO CONVERT CRUDE ASCOMYCIN INTO PURIFIED PIMECROLIMUS<br/>[FR] PROCÉDÉ DE CONVERSION D'ASCOMYCINE BRUTE EN PIMÉCROLIMUS PURIFIÉ
  申请人：MEDA PHARMA GMBH & CO KG

  公开号：WO2018202733A1

  公开（公告）日：2018-11-08

  The present disclosure is directed to an improved process to convert crude ascomycin to purified pimecrolimus. Crude ascomycin is chlorinated with triphenylphosphine and N-chlorosuccinimide (NCS) to yield crude pimecrolimus, which is then purified further by HPLC and subsequent crystallization. The processes of the present disclosure enable the removal of close homologs of pimecrolimus by high-pressure liquid chromatography without prior purification of the ascomycin starting material. This improvement may make the conversion of ascomycin to pimecrolimus industrially applicable and less expensive.

  本公开涉及一种改进的工艺，将粗制曲霉素转化为纯化皮米克罗霉素。粗制曲霉素经三苯基膦和N-氯代琥珀酰亚胺（NCS）氯化，得到粗制皮米克罗霉素，然后通过高效液相色谱和随后的结晶进一步纯化。本公开的工艺使得可以通过高压液相色谱去除皮米克罗霉素的近同源物，而无需事先对曲霉素起始物料进行纯化。这一改进可能使得从曲霉素转化为皮米克罗霉素具有工业应用性且更为经济。
• 一种吡美莫司的制备方法
  申请人：博瑞生物医药（苏州）股份有限公司

  公开号：CN106854228B

  公开（公告）日：2020-05-29

  本发明涉及一种适合工业化应用的从子囊霉素制备吡美莫司的方法。本发明提供的方法收率显著提高，可通过结晶方法纯化所获得的吡美莫司，而不需要通过柱色谱纯化。
• PROCESS FOR PREPARING PIMECROLIMUS
  申请人：Medichem, S.A.

  公开号：EP3178824A1

  公开（公告）日：2017-06-14

  The present invention is related to an improved industrially applicable process for preparing pimecrolimus from ascomycin. This process shows significantly high yields, so that purification of the pimecrolimus can be accomplished by crystallization, not requiring for example of chromatographic purifications.

  本发明涉及一种从曲霉素制备匹美沙酮的改进工业应用过程。该过程显示出极高的产量，因此匹美沙酮的纯化可以通过结晶实现，不需要例如色谱纯化。
• PHOSPHONATE COMPOUNDS HAVING IMMUNO-MODULATORY ACTIVITY
  申请人：Cannizzaro Carina

  公开号：US20090227543A1

  公开（公告）日：2009-09-10

  The invention is related to phosphonate substituted compounds having immuno-modulatory activity, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

  本发明涉及磷酸酯取代化合物，具有免疫调节活性，含有这种化合物的组合物，以及包括这种化合物的给药的治疗方法，还涉及用于制备这种化合物的有用过程和中间体。
• ANTI-INFLAMMATORY PHOSPHONATE COMPOUNDS
  申请人：Cannizzaro Carina

  公开号：US20090247488A1

  公开（公告）日：2009-10-01

  The invention is related to phosphorus substituted anti-inflammatory compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

  本发明涉及磷取代的抗炎化合物、含有这种化合物的组合物、包括给药这种化合物的治疗方法，以及用于制备这种化合物的有用过程和中间体。