(1S,2R,3R,4aR,6aS,7R,8R,10aR,10bR,12aR)-2-hydroxy-3-methoxy-1,6a,8,10a-tetramethyl-8-((R)-3-methylbutan-2-yl)-2,3,4,6,6a,7,8,9,10,10a,10b,11,12,12a-tetradeca-hydro-1H-1,4a-(methanooxymethano)chrysene-7-carboxylic acid | 1140751-11-6

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: (1S,2R,3R,4aR,6aS,7R,8R,10aR,10bR,12aR)-2-hydroxy-3-methoxy-1,6a,8,10a-tetramethyl-8-((R)-3-methylbutan-2-yl)-2,3,4,6,6a,7,8,9,10,10a,10b,11,12,12a-tetradeca-hydro-1H-1,4a-(methanooxymethano)chrysene-7-carboxylic acid
• 英文别名: (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-8-[(1R)-1,2-dimethylpropyl]-15-hydroxy-14-methoxy-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid；(1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-8-[(1R)-1,2-dimethylpropyl]-15-hydroxy-14-methoxy-1,6,6a,7,8,9,10,10a,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid；(1R,5S,6R,7R,10R,11R,14R,15S,20R,21R)-21-hydroxy-20-methoxy-5,7,10,15-tetramethyl-7-[(2R)-3-methylbutan-2-yl]-17-oxapentacyclo[13.3.3.01,14.02,11.05,10]henicos-2-ene-6-carboxylic acid
• CAS: 1140751-11-6
• 化学式: C₃₁H₅₀O₅
• 分子量: 502.735
• InChiKey: VIZJSSRXFPODHT-QDBJBGNFSA-N

物化性质

• 熔点：
  266.7-267.3 °C ()
• 沸点：
  605.4±55.0 °C (Predicted,Press: 760 Torr)
• 密度：
  1.13±0.1 g/cm³ (Predicted,Temp: 20 °C; Press: 760 Torr)
• pKa：
  4.70±0.70 (Predicted,Most Acidic Temp: 25 °C)

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  36
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.9
• 拓扑面积：
  76
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (1S,2R,3R,4aR,6aS,7R,8R,10aR,10bR,12aR)-2-hydroxy-3-methoxy-1,6a,8,10a-tetramethyl-8-((R)-3-methylbutan-2-yl)-2,3,4,6,6a,7,8,9,10,10a,10b,11,12,12a-tetradeca-hydro-1H-1,4a-(methanooxymethano)chrysene-7-carboxylic acid 在 三氟化硼乙醚 、 sodium hydride 、 potassium carbonate 、 一水合肼 、 溶剂黄146 作用下， 以 乙醇 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 tert-butyl (2R)-2-[[(1R,5S,6R,7R,10R,11R,14R,15S,20R,21R)-6-[(4-methoxyphenyl)methoxycarbonyl]-5,7,10,15-tetramethyl-7-[(2R)-3-methylbutan-2-yl]-20-(5-pyridin-4-yl-1,2,4-triazol-1-yl)-17-oxapentacyclo[13.3.3.01,14.02,11.05,10]henicos-2-en-21-yl]oxymethyl]-2-methylpyrrolidine-1-carboxylate
  参考文献：
  名称：

  Synthesis and biological evaluation of antifungal derivatives of enfumafungin as orally bioavailable inhibitors of β-1,3-glucan synthase

  摘要：

  Orally bioavailable inhibitors of beta-(1,3)-D-glucan synthase have been pursued as new, broad-spectrum fungicidal therapies suitable for treatment in immunocompromised patients. Toward this end, a collaborative medicinal chemistry program was established based on semisynthetic derivatization of the triterpenoid glycoside natural product enfumafungin in order to optimize in vivo antifungal activity and oral absorption properties. In the course of these studies, it was hypothesized that the pharmacokinetic properties of the semisynthetic enfumafungin analog 3 could be improved by tethering the alkyl groups proximal to the basic nitrogen of the C3-aminoether side chain into an azacyclic system, so as to preclude oxidative N-demethylation. The results of this research effort are disclosed herein. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.05.031
• 作为产物：
  描述：

  (1R,5S,6R,7R,10R,11R,14R,15S,20R,21R)-20-acetyloxy-5,7,10,15-tetramethyl-7-[(2R)-3-methylbutan-2-yl]-21-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-17-oxapentacyclo[13.3.3.01,14.02,11.05,10]henicos-2-ene-6-carboxylic acid 生成 (1S,2R,3R,4aR,6aS,7R,8R,10aR,10bR,12aR)-2-hydroxy-3-methoxy-1,6a,8,10a-tetramethyl-8-((R)-3-methylbutan-2-yl)-2,3,4,6,6a,7,8,9,10,10a,10b,11,12,12a-tetradeca-hydro-1H-1,4a-(methanooxymethano)chrysene-7-carboxylic acid
  参考文献：
  名称：

  Antifungal agents

  摘要：

  本文披露了恩福马富金的新型衍生物，以及它们的药用盐、水合物和前药。还公开了包含这些化合物的组合物、制备这些化合物的方法以及将这些化合物用作抗真菌剂和/或(1,3)-β-D-葡聚糖合酶抑制剂的方法。这些公开的化合物、它们的药用盐、水合物和前药，以及包含这些化合物、盐、水合物和前药的组合物，可用于治疗和/或预防真菌感染及相关疾病和病况。

  公开号：

  US20100113439A1

文献信息

• Ibrexafungerp: An orally active β-1,3-glucan synthesis inhibitor
  作者：James M. Apgar、Robert R. Wilkening、Dann L. Parker、Dongfang Meng、Kenneth J. Wildonger、Donald Sperbeck、Mark L. Greenlee、James M. Balkovec、Amy M. Flattery、George K. Abruzzo、Andrew M. Galgoci、Robert A. Giacobbe、Charles J. Gill、Ming-Jo Hsu、Paul Liberator、Andrew S. Misura、Mary Motyl、Jennifer Nielsen Kahn、Maryann Powles、Fred Racine、Jasminka Dragovic、Weiming Fan、Robin Kirwan、Shu Lee、Hao Liu、Ahmed Mamai、Kingsley Nelson、Michael Peel

  DOI：10.1016/j.bmcl.2020.127661

  日期：2021.1

  reported medicinal chemistry efforts that identified MK-5204, an orally efficacious β-1,3-glucan synthesis inhibitor derived from the natural product enfumafungin. Further extensive optimization of the C2 triazole substituent identified 4-pyridyl as the preferred replacement for the carboxamide of MK-5204, leading to improvements in antifungal activity in the presence of serum, and increased oral exposure

  我们之前报道了确定 MK-5204 的药物化学工作，MK-5204 是一种口服有效的 β-1,3-葡聚糖合成抑制剂，来源于天然产物恩夫马芬净。C2 三唑取代基的进一步优化确定 4-吡啶基是 MK-5204 甲酰胺的首选替代品，导致在血清存在下的抗真菌活性提高，并增加口服暴露。在这个新发现的 C2 取代基的存在下重新优化 C3 处的氨基醚，证实（R) MK-5204 的叔丁基甲基氨基醚提供了这两个关键参数的最佳平衡，最终发现了 ibrexafungerp，目前正处于 III 期临床试验。Ibrexafungerp 在小鼠感染模型中显示出显着改善的口服功效，使其成为临床开发的优秀候选药物，作为念珠菌和曲霉菌感染的口服治疗药物。
• MK-5204: An orally active β-1,3-glucan synthesis inhibitor
  作者：James M. Apgar、Robert R. Wilkening、Dann L. Parker、Dongfang Meng、Kenneth J. Wildonger、Donald Sperbeck、Mark L. Greenlee、James M. Balkovec、Amy M. Flattery、George K. Abruzzo、Andrew M. Galgoci、Robert A. Giacobbe、Charles J. Gill、Ming-Jo Hsu、Paul Liberator、Andrew S. Misura、Mary Motyl、Jennifer Nielsen Kahn、Maryann Powles、Fred Racine、Jasminka Dragovic、Weiming Fan、Robin Kirwan、Shu Lee、Hao Liu、Ahmed Mamai、Kingsley Nelson、Michael Peel

  DOI：10.1016/j.bmcl.2020.127357

  日期：2020.9

  Our previously reported efforts to produce an orally active β-1,3-glucan synthesis inhibitor through the semi-synthetic modification of enfumafungin focused on replacing the C2 acetoxy moiety with an aminotetrazole and the C3 glycoside with a N,N-dimethylaminoether moiety. This work details further optimization of the C2 heterocyclic substituent, which identified 3-carboxamide-1,2,4-triazole as a replacement

  我们先前报道的通过恩富马芬的半合成修饰来生产口服活性β-1,3-葡聚糖合成抑制剂的努力集中在用氨基四唑代替C2乙酰氧基部分和用N，N-二甲基氨基醚部分代替C3糖苷。这项工作详细介绍了C2杂环取代基的进一步优化，该取代基确定了3-羧酰胺-1,2,4-三唑是具有可比的抗真菌活性的氨基四唑的替代品。C2处的羧酰胺三唑或C3处的氨基醚烷基化均无法显着改善口服功效。但是，用t取代异丙基α-氨基取代基丁基，改善口腔暴露，同时保持抗真菌活性。这两种结构修饰产生了MK-5204，其在散播念珠菌病的鼠模型中证明了针对念珠菌的广谱活性和强大的口服功效，而没有观察到先前铅的N-脱烷基反应。
• [EN] ANTIFUNGAL AGENTS<br/>[FR] AGENTS ANTIFONGIQUES
  申请人：MERCK SHARP & DOHME

  公开号：WO2010019203A8

  公开（公告）日：2011-03-17
• Ibrexafungerp. 1,3-Beta-Glucan synthase inhibitor, Triterpenoid antifungal agent
  作者：R. Thakare、A. Dasgupta、S. Chopra

  DOI：10.1358/dof.2019.44.4.2962844

  日期：——

  Fungal pathogens are responsible for a large number of mild to severe infections worldwide resulting in 1.6 million deaths. With the rapid emergence of drug resistance, the treatment of fungal infections is rapidly becoming unmanageable. Thus, the discovery and development of novel antifungal drugs is an unmet need of the hour. In this context, ibrexafungerp (SCY-078; SCYNEXIS) is the first orally bioavailable agent that has activity against beta-glucan synthase, an essential component of the cell wall. It has broad-spectrum activity against a wide range of Candida sp, including those that are resistant to echinocandins. In addition, ibrexafungerp exhibits broad-spectrum fungicidal activity including against multidrug-resistant strains, possesses high tissue penetration and exhibits flexible dosing options including via oral and intravenous routes. The U.S. Food and Drug Administration has granted both qualified infectious disease product and fast track designations for the oral formulation of ibrexafungerp for the treatment and prevention of recurrent vulvovaginal candidiasis.
• Synthesis of Antifungal Glucan Synthase Inhibitors from Enfumafungin
  作者：Yong-Li Zhong、Donald R. Gauthier、Yao-Jun Shi、Mark McLaughlin、John Y. L. Chung、Philippe Dagneau、Benjamin Marcune、Shane W. Krska、Richard G. Ball、Robert A. Reamer、Nobuyoshi Yasuda

  DOI：10.1021/jo300046v

  日期：2012.4.6

  An efficient, new, and scalable semisynthesis of glucan synthase inhibitors 1 and 2 from the fermentation product enfumafungin 3 is described. The highlights of the synthesis include a high-yielding ether bond-forming reaction between a bulky sulfamidate 17 and alcohol 4 and a remarkably chemoselective, improved palladium(II)-mediated Corey-Yu allylic oxidation at the highly congested C-12 position of the enfumafungin core. Multi-hundred gram quantities of the target drug candidates 1 and 2 were prepared, in 12 linear steps with 25% isolated yield and 13 linear steps with 22% isolated yield, respectively.