PPI-2458 | 431077-35-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: PPI-2458
• 英文别名: [(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl] N-[(2R)-1-amino-3-methyl-1-oxobutan-2-yl]carbamate；(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl [(R)-1-amino-3-methyl-1-oxobutan-2-yl]carbamate；(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (R)-1-amino-3-methyl-1-oxobutan-2-ylcarbamate；Metapro
• CAS: 431077-35-9
• 化学式: C₂₂H₃₆N₂O₆
• 分子量: 424.538
• InChiKey: QBDVVYNLLXGUGN-XGTBZJOHSA-N

物化性质

• 沸点：
  578.9±50.0 °C(Predicted)
• 密度：
  1.17±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  30
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  116
• 氢给体数：
  2
• 氢受体数：
  6

制备方法与用途

PPI-2458 是一种强效、口服活性、选择性且不可逆的蛋氨酸氨基肽酶-2（MetAP-2）抑制剂，适用于关节炎和淋巴瘤的研究。[1][2]

反应信息

• 作为反应物：
  描述：

  PPI-2458 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 2.0h， 以54%的产率得到[(1R,2S,3S,4R)-4-(chloromethyl)-4-hydroxy-3-[(3R)-3-hydroxy-6-methylhepta-1,5-dien-2-yl]-2-methoxycyclohexyl] N-[(2R)-1-amino-3-methyl-1-oxobutan-2-yl]carbamate
  参考文献：
  名称：

  Orally Active Fumagillin Analogues: Transformations of a Reactive Warhead in the Gastric Environment

  摘要：

  Semisynthetic analogues of fumagillin, 1, inhibit methionine aminopeptidase-2 (MetAP2) and have entered the clinic for the treatment of cancer. An optimized fumagillin analogue, 3 (PPI-2458), was found to be orally active, despite containing a spiroepoxide function that formed a covalent linkage to the target protein. In aqueous acid, 3 underwent ring-opening addition of water and HCl, leading to four products, 4-7, which were characterized in detail. The chlorohydrin, but not the diol, products inhibited MetAP2 under weakly basic conditions, suggesting reversion to epoxide as a step in the mechanism. In agreement, chlorohydrin 6 was shown to revert rapidly to 3 in rat plasma. In an ex vivo assay, rats treated with purified acid degradants demonstrated inhibition of MetAP2 that correlated with the biochemical activity of the compounds. Taken together, the results indicate that degradation of the parent compound was compensated by the formation of active equivalents leading to a pharmacologically useful level of MetAP2 inhibition.

  DOI：

  10.1021/ml3003633
• 作为产物：
  描述：

  5-甲氧基-4-[2-甲基-3-(3-甲基丁-2-烯基)环氧乙烷-2-基]-1-氧杂螺[2.5]辛烷-6-醇 在 4-二甲氨基吡啶 N,N-二异丙基乙胺 作用下， 以 乙醇 、 二氯甲烷 、 乙酸乙酯 为溶剂， 生成 PPI-2458
  参考文献：
  名称：

  [EN] OXASPIRO [2.5] OCTANE DERIVATIVES AND ANALOGS
  [FR] DÉRIVÉS D'OXASPIRO[2.5]OCTANE ET ANALOGUES

  摘要：

  这项发明提供了氧杂螺[2.5]辛烷衍生物和类似物，其制备方法，中间体，药物组合物以及在治疗各种疾病和状况中的用途，例如超重和肥胖。

  公开号：

  WO2012122264A1

文献信息

• Carbamate Analogues of Fumagillin as Potent, Targeted Inhibitors of Methionine Aminopeptidase-2
  作者：Christopher C. Arico-Muendel、Dennis R. Benjamin、Teresa M. Caiazzo、Paolo A. Centrella、Brooke D. Contonio、Charles M. Cook、Elisabeth G. Doyle、Gerhard Hannig、Matthew T. Labenski、Lily L. Searle、Kenneth Lind、Barry A. Morgan、Gary Olson、Christopher L. Paradise、Christopher Self、Steven R. Skinner、Barbara Sluboski、Jennifer L. Svendsen、Charles D. Thompson、William Westlin、Kerry F. White

  DOI：10.1021/jm901260k

  日期：2009.12.24

  approach to antiangiogenic therapy. We describe the synthesis and activity of fumagillin analogues that address the pharmacokinetic and safety liabilities of earlier candidates in this compound class. Two-step elaboration of fumagillol with amines yielded a diverse series of carbamates at C6 of the cyclohexane spiroepoxide. The most potent of these compounds exhibited subnanomolar inhibition of cell

  抑制蛋氨酸氨基肽酶2（MetAP2）代表一种抗血管生成治疗的新方法。我们描述了烟曲霉素类似物的合成和活性，解决了该化合物类别中较早候选药物的药代动力学和安全性问题。烟曲霉酚与胺的两步精制在环己烷螺环氧化物的C6处产生了一系列氨基甲酸酯。这些化合物中最有效的化合物在HUVEC和BAEC分析中表现出对细胞增殖的亚纳摩尔抑制作用。尽管在此位置可以耐受多种功能，但α-三取代胺的抑制活性显着降低，可以通过基于已知的烟曲霉素-MetAP2晶体结构进行建模来使其合理化。这些研究得出的先导化合物（3 R，4S，5 S，6 R）-5-甲氧基-4-（（2 R，3 R）-2-甲基-3-（3-甲基丁-2-烯基）环氧乙烷-2-基）-1-氧杂螺[ 2.5] octan-6-基（R）-1-氨基-3-甲基-1-氧丁烷-2-基氨基甲酸酯（PPI-2458）相对于较早的临床候选药物TNP-470表现出改善的药代动力学特征，并
• Metabolites of PPI-2458, a Selective, Irreversible Inhibitor of Methionine Aminopeptidase-2: Structure Determination and In Vivo Activity
  作者：Christopher C. Arico-Muendel、Bruce Belanger、Dennis Benjamin、Heather S. Blanchette、Teresa M. Caiazzo、Paolo A. Centrella、Jennifer DeLorey、Elisabeth G. Doyle、Ulrike Gradhand、Sarah T. Griffin、Susan Hill、Matthew T. Labenski、Barry A. Morgan、Gary O’Donovan、Kavirayani Prasad、Steven Skinner、Nazbeh Taghizadeh、Charles D. Thompson、James Wakefield、William Westlin、Kerry F. White

  DOI：10.1124/dmd.112.048355

  日期：2013.4

  The natural product fumagillin exhibits potent antiproliferative and antiangiogenic properties. The semisynthetic analog PPI-2458, [(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl] N -[(2R)-1-amino-3-methyl-1-oxobutan-2-yl]carbamate, demonstrates rapid inactivation of its molecular target, methionine aminopeptidase-2 (MetAP2), and good efficacy in several rodent models of cancer and inflammation with oral dosing despite low apparent oral bioavailability. To probe the basis of its in vivo efficacy, the metabolism of PPI-2458 was studied in detail. Reaction phenotyping identified CYP3A4/5 as the major source of metabolism in humans. Six metabolites were isolated from liver microsomes and characterized by mass spectrometry and nuclear resonance spectroscopy, and their structures were confirmed by chemical synthesis. The synthetic metabolites showed correlated inhibition of MetAP2 enzymatic activity and vascular endothelial cell growth. In an ex vivo experiment, MetAP2 inhibition in white blood cells, thymus, and lymph nodes in rats after single dosing with PPI-2458 and the isolated metabolites was found to correlate with the in vitro activity of the individual species. In a phase 1 clinical study, PPI-2458 was administered to patients with non-Hodgkin lymphoma. At 15 mg administered orally every other day, MetAP2 in whole blood was 80% inactivated for up to 48 hours, although the exposure of the parent compound was only ∼ 10% that of the summed cytochrome P450 metabolites. Taken together, the data confirm the participation of active metabolites in the in vivo efficacy of PPI-2458. The structures define a metabolic pathway for PPI-2458 that is distinct from that of TNP-470 ([(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl] N -(2-chloroacetyl)carbamate). The high level of MetAP2 inhibition achieved in vivo supports the value of fumagillin-derived therapeutics for angiogenic diseases.

  天然产物福马吉林具有强效的抗增殖和抗血管生成特性。The semisynthetic analog PPI-2458, [(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl]N -[(2R)-1-氨基-3-甲基-1-氧代丁-2-基]氨基甲酸酯可快速灭活其分子靶标蛋氨酸氨肽酶-2 (MetAP2)，并且尽管口服生物利用度较低，但在多种癌症和炎症啮齿动物模型中口服具有良好疗效。为了探究其体内疗效的基础，我们对 PPI-2458 的代谢进行了详细研究。反应表型确定 CYP3A4/5 是人体代谢的主要来源。从肝脏微粒体中分离出了六种代谢物，并通过质谱和核共振光谱对其进行了表征，还通过化学合成确认了它们的结构。合成的代谢物对 MetAP2 酶活性和血管内皮细胞生长有相关的抑制作用。在一项体内外实验中，大鼠在单次服用 PPI-2458 和分离出的代谢物后，其白细胞、胸腺和淋巴结中的 MetAP2 抑制作用与单个物种的体外活性相关。在一项 1 期临床研究中，PPI-2458 被用于非霍奇金淋巴瘤患者。每隔一天口服 15 毫克，全血中 MetAP2 的灭活率为 80%，持续时间长达 48 小时，但母体化合物的暴露量仅为细胞色素 P450 代谢物总和的 10%。总之，这些数据证实了活性代谢物参与了 PPI-2458 的体内药效。这些结构确定了 PPI-2458 不同于 TNP-470 （[(3R,4S,5S,6R)-5-甲氧基-4-[(2R,3R)-2-甲基-3-(3-甲基丁-2-烯基)环氧乙烷-2-基]-1-氧杂螺[2.5]辛烷-6-基]）的代谢途径。N-(2-氯乙酰基)氨基甲酸酯）。在体内实现的对 MetAP2 的高水平抑制支持了烟曲霉素衍生疗法治疗血管生成疾病的价值。
• Therapeutic agents and methods of use thereof for the modulation of angiogenesis
  申请人：Praecis Pharmaceuticals, Inc.

  公开号：US07037890B2

  公开（公告）日：2006-05-02

  The present invention provides angiogenesis inhibitor compounds comprising a MetAP-2 inhibitory core coupled to a peptide, as well as pharmaceutical compositions comprising the angiogenesis inhibitor compounds and a pharmaceutically acceptable carrier. The present invention also provides methods of treating an angiogenic disease, e.g., cancer, in a subject by administering to the subject a therapeutically effective amount of one or more of the angiogenesis inhibitor compounds of the invention.

  本发明提供了一种包括MetAP-2抑制核心结合肽的血管生成抑制剂化合物，以及包括该血管生成抑制剂化合物和药学上可接受的载体的制药组合物。本发明还提供了一种通过向受试者施用本发明的一种或多种血管生成抑制剂化合物的治疗有效量来治疗血管生成性疾病（例如癌症）的方法。
• Oxaspiro[2.5]Octane Derivatives and Analogs
  申请人：Vath James E.

  公开号：US20150045427A1

  公开（公告）日：2015-02-12

  The invention provides oxaspiro[2.5]octane derivatives and analogs, methods for preparation thereof, intermediates thereto, pharmaceutical compositions, and uses thereof in the treatment of various disorders and conditions, such as overweight and obesity.

  本发明提供了氧杂螺[2.5]辛烷衍生物和类似物，其制备方法，中间体，制药组合物以及在治疗各种疾病和病况（例如超重和肥胖）中的应用。
• Methods of treating ischemic organ damage and other disorders
  申请人：Zafgen, Inc.

  公开号：US10231946B2

  公开（公告）日：2019-03-19

  The invention generally relates to methods of treating a patient suffering from renal disorders or other disorders related to low levels of sRAGE, and/or low levels of adiponectin (e.g., high molecular weight adiponectin) and/or high levels of thrombomodulin, using effective of amounts of a MetAP-2 inhibitor.

  本发明一般涉及使用有效量的 MetAP-2 抑制剂治疗患有肾脏疾病或其他与低水平 sRAGE 和/或低水平脂肪连通素（如高分子量脂肪连通素）和/或高水平血栓调节蛋白相关疾病的患者的方法。