拉坦前列素硝酸酯 | 860005-21-6

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 中文名称: 拉坦前列素硝酸酯
• 中文别名: 硝基拉坦前列腺素
• 英文名称: 4-(nitrooxy)butyl [1α(Z),2β(R),3α,5α]-7-[3,5-dihydroxy-2-((3R)-3-hydroxy-5-phenylpentyl)cyclopentyl]-5-heptenoate
• 英文别名: 4-(nitrooxy)butyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate；latanoprostene bunod；[1R-[1α (Z), 2β (R*), 3α, 5α]]-7-[3,5-dihydroxy-2-(3-hydroxy-5-phenylpentyl)cyclopentyl]-5-heptenoic acid 4-(nitrooxy)butyl ester；4-nitrooxybutyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]hept-5-enoate
• CAS: 860005-21-6
• 化学式: C₂₇H₄₁NO₈
• 分子量: 507.624
• InChiKey: LOVMMUBRQUFEAH-UIEAZXIASA-N

物化性质

• 沸点：
  658.3±55.0 °C(Predicted)
• 密度：
  1.178±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  36
• 可旋转键数：
  18
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  142
• 氢给体数：
  3
• 氢受体数：
  8

ADMET

代谢

在眼部表面局部给药后，拉坦前列素苯并嗪通过角膜内酯酶的快速羧酸酯水解，分解为拉坦前列酸和丁二醇单硝酸盐。拉坦前列酸进入系统循环后，主要通过肝脏通过脂肪酸β-氧化代谢为1,2-去甲和1,2,3,4-四去甲代谢物。丁二醇单硝酸盐进一步代谢（还原）为1,4-丁二醇和一氧化氮（NO）。此外，这个1,4-丁二醇代谢物进一步氧化为琥珀酸，然后主要作为三羧酸（TCA）循环中细胞有氧呼吸的一个组成部分被摄取。

Upon topical administration at the ocular surface, latanoprostene bunod undergoes rapid carboxyl ester hydrolysis by endogenous corneal esterases into latanoprost acid and butanediol mononitrate. After the latanoprost acid reaches the systemic circulation, it is largely metabolized by the liver to the 1,2-dinor and 1,2,3,4-tetranor metabolites by way of fatty acid beta-oxidation. The butanediol monohidrate undergoes further metabolism (reduction) to 1,4-butanediol and nitric oxide (NO). Furthermore, this 1,4-butanediol metabolite is further oxidized to succinic acid that is subsequently then primarily taken up as a component in the tricarboxylic acid (TCA) cycle in cellular aerobic respiration.

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：目前没有关于在母乳喂养期间使用拉坦前列素丁钠的信息。由于药物在眼睛局部应用后血浆中浓度极低且半衰期短，它不太可能达到婴儿的母乳或血液中，也不会对哺乳婴儿造成任何不良影响。专业指南认为，在母乳喂养期间使用前列腺素眼药水是可以接受的。为了进一步减少眼药水使用后进入母乳的药物量，可以在眼角处对泪囊施加压力1分钟或更长时间，然后用吸收性纸巾去除多余的溶液。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:No information is available on the use of latanoprostene bunod during breastfeeding. Because of the extremely low levels in plasma after application to the eye and short half-life, it is not likely to reach the breastmilk or bloodstream of the infant or to cause any adverse effects in breastfed infants. Professional guidelines consider prostaglandin eye drops acceptable during breastfeeding. To further diminish the amount of drug that reaches the breastmilk after using eye drops, place pressure over the tear duct by the corner of the eye for 1 minute or more, then remove the excess solution with an absorbent tissue. ◉ 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)

吸收、分配和排泄

• 吸收

在一项对22名健康受试者进行28天监测的研究中，每日一次在早上双侧各滴一滴的剂量下，拉坦前列素丁诺酸（检测下限LLOQ为10.0 pg/mL）或丁二醇单硝酸酯（检测下限LLOQ为200 pg/mL）的血浆浓度在治疗第1天和第28天均未达到可量化水平。拉坦前列酸的平均最大血浆浓度（Tmax）在治疗第1天和第28天大约在给药后5分钟。拉坦前列酸的平均最大血浆浓度（Cmax）（检测下限LLOQ为30 pg/mL）在第1天和第28天分别为59.1 pg/mL。

In a study with 22 healthy subjects monitored for 28 days, there were no quantifiable plasma concentrations of latanoprostene bunod (Lower Limit Of Quantitation, LLOQ, of 10.0 pg/mL) or butanediol mononitrate (LLOQ of 200 pg/mL) post daily dose of one drop bilaterally in the morning on Day 1 and 28. The mean time of maximum plasma concentration (Tmax) for latanoprost acid was about 5 minutes post dosage on both Day 1 and 28 of therapy. The mean maximum plasma concentrations (Cmax) of latanoprost acid (LLOQ of 30 pg/mL) were 59.1 pg/mL on Day 1 and 28, respectively.

来源:DrugBank

吸收、分配和排泄

• 消除途径

拉坦前列酸是拉坦前列素丁酸的成分，主要由肝脏代谢并在尿液中主要排出。

The latanoprost acid component of latanoprostene bunod is predominantly metabolized by the liver and excreted primarily in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

目前还没有在人类中进行正式的眼部分布研究。

Unfortunately there have been no formal ocular distribution studies performed in humans at this time.

来源:DrugBank

吸收、分配和排泄

• 清除

由于拉坦前列腺酸在普通眼部给药后15分钟内，在大多数研究对象的血浆中的浓度降至30 pg/mL的定量下限（LLOQ）以下，因此认为拉坦前列腺酸从人血浆中清除是迅速的。

Since latanoprost acid plasma concentration dropped below the LLOQ (Lower Limit Of Quantitation) of 30 pg/mL in the majority of study subjects by 15 minutes following ordinary ocular administration, the elimination of latanoprost acid from human plasma is considered rapid.

来源:DrugBank

反应信息

• 作为产物：
  描述：

  4-bromobutyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate 在 silver nitrate 作用下， 以 乙腈 为溶剂， 反应 55.0h， 生成 拉坦前列素硝酸酯
  参考文献：
  名称：

  PROCESS FOR THE PREPARATION OF LATANOPROSTENE BUNOD AND INTERMEDIATE THEREOF AND COMPOSITIONS COMPRISING THE SAME

  摘要：

  制备拉坦前列素布诺酯和从该过程制备的中间体的方法。另外还有具有高纯度拉坦前列素布诺酯的拉坦前列素布诺酯组合物。

  公开号：

  US20220024849A1

文献信息

• [EN] PROSTAGLANDIN NITROOXYDERIVATIVES<br/>[FR] NITRO-OXY-DERIVES DE LA PROSTAGLANDINE
  申请人：NICOX SA

  公开号：WO2005068421A1

  公开（公告）日：2005-07-28

  Prostaglandin nitrooxyderivatives having improved pharmacological activity and enhanced tolerability are described. They can be employed for the treatment of glaucoma and ocular hypertension.

  描述了具有改善药理活性和增强耐受性的前列腺素硝氧衍生物。它们可用于治疗青光眼和眼压增高。
• [EN] NITRIC OXIDE RELEASING PROSTAGLANDIN DERIVATIVES FOR TREATING NORMAL TENSION GLAUCOMA<br/>[FR] DÉRIVÉS DE PROSTAGLANDINE LIBÉRANT DE L'OXYDE NITRIQUE POUR LE TRAITEMENT DU GLAUCOME À TENSION NORMALE
  申请人：BAUSCH & LOMB

  公开号：WO2018087092A1

  公开（公告）日：2018-05-17

  This invention provides a method of lowering intraocular pressure in a patient having normal tension glaucoma, comprising contacting an eye of a subject having normal tension glaucoma with a pharmaceutical composition comprising an effective amount of Nitric Oxide releasing prostaglandin derivatives of formula (I).

  这项发明提供了一种降低正常张力青光眼患者眼内压的方法，包括将含有一定量一氧化氮释放前列腺素衍生物（式（I））的药物组合物与患有正常张力青光眼的受试者的眼部接触。
• PROSTAGLANDIN ANALOGS AND USES THEREOF
  申请人：Lifex Biolabs, Inc.

  公开号：US20210139435A1

  公开（公告）日：2021-05-13

  The present invention relates to pharmaceutical composition for the prevention or treatment of a disease, disorder, or condition associated with Nurr1, including, as an active ingredient, a prostaglandin analog or a pharmaceutically acceptable salt thereof, wherein the compound has excellent effects in inducing Nurr1, and thus, can be useful as a pharmaceutical composition for the prevention or treatment of a disease, disorder, or condition associated with Nurr1, in particular, cancer, autoimmune disease such as rheumatoid arthritis, schizophrenia, manic depression and neurodegenerative disease such as Alzheimers disease or Parkinson's disease.

  本发明涉及一种药物组合物，用于预防或治疗与Nurr1相关的疾病、紊乱或状况，其中包括作为活性成分的前列腺素类似物或其药学上可接受的盐，该化合物具有良好的诱导Nurr1的效果，因此，可用作预防或治疗与Nurr1相关的疾病、紊乱或状况的药物组合物，特别是癌症、自身免疫性疾病如类风湿关节炎、精神分裂症、躁郁症以及神经退行性疾病如阿尔茨海默病或帕金森病。
• Prostaglandin derivatives
  申请人：Nicox S.A.

  公开号：US07273946B2

  公开（公告）日：2007-09-25

  Prostaglandin nitroderivatives having improved pharmacological activity and enhanced tolerability are described. They can be employed for the treatment of glaucoma and ocular hypertension.

  本文描述了具有改善药理活性和增强耐受性的前列腺素硝基衍生物。它们可用于治疗青光眼和眼压增高。
• PROSTAGLANDIN DERIVATIVES
  申请人：Ongini Ennio

  公开号：US20090030076A1

  公开（公告）日：2009-01-29

  Prostaglandin nitroderivatives having improved pharmacological activity and enhanced tolerability are described. They can be employed for the treatment of glaucoma and ocular hypertension.

  本文描述了具有改善药理活性和增强耐受性的前列腺素硝基衍生物。它们可用于治疗青光眼和眼压增高。