(R)-N-(2,4-二羟基-3,3-二甲基-1-氧代丁基)-beta-丙氨酸甲酯 | 50692-78-9

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 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
• 中文名称: (R)-N-(2,4-二羟基-3,3-二甲基-1-氧代丁基)-beta-丙氨酸甲酯
• 中文别名: 3-溴-5-氟-2-羟基吡喃并啶；泛酸钙杂质1
• 英文名称: methyl pantothenate
• 英文别名: methyl 3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]propanoate
• CAS: 50692-78-9
• 化学式: C₁₀H₁₉NO₅
• 分子量: 233.265
• InChiKey: XUOLPZAHXIRZLN-QMMMGPOBSA-N

物化性质

• 沸点：
  120-125 °C(Press: 0.01 Torr)
• 密度：
  1.175±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)：
  -0.7
• 重原子数：
  16
• 可旋转键数：
  7
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  95.9
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (R)-N-(2,4-二羟基-3,3-二甲基-1-氧代丁基)-beta-丙氨酸甲酯 在 吡啶 、 三甲基氯硅烷 、 lithium bromide 作用下， 以 二氯甲烷 为溶剂， 生成 S-propyl 3-[(2R)-2-hydroxy-3,3-dimethyl-4-phosphonooxybutyrylamino]thiopropionate
  参考文献：
  名称：

  Synthesis of Novel Analogs of Acetyl Coenzyme A: Mimics of Enzyme Reaction Intermediates

  摘要：

  An improved method for the synthesis of analogs of coenzyme A (CoA) and its thioesters, which are modified in the thiol or thioester moiety, has been developed using a combination of chemical and enzymatic reactions, The enzymes catalyzing the last two steps of CoA biosynthesis were used to prepare a CoA analog (1c) in which an amide bond is replaced by a thioester bond and the thiol group is replaced by a methyl group. Reaction of 1c with a primary amine in aqueous solution results in aminolysis of the thioester linkage to form the desired CoA analog. Reaction with different amines permits the introduction of a variety of functional groups in place of the nor mal thiol or thioester group. This methodology has been used in the synthesis of five new analogs of acetyl-CoA in which the thioester sulfur is replaced by a methylene group and the acetyl group is replaced by carboxylate (14a), nitro (14b), carboxamide (14c), methyl sulfoxide (14d), and methyl sulfone (14e) groups. 14a-c were designed to mimic the possible enolate or enol intermediate in the reaction of citrate synthase and related enzymes. 14a and 14c are potent inhibitors of citrate synthase, with K-i values 1000- and 570-fold lower than the K-m for acetyl-CoA, respectively. CD titrations indicate that 14a and 14c have low affinity for citrate synthase in the absence of oxaloacetate, consistent with their recognition as enol or enolate analogs. 14b is a poor inhibitor of citrate synthase, with affinity slightly lower than that for acetyl-CoA. These results are consistent with generation of the enol form of acetyl-CoA as the nucleophilic intermediate in the reaction of citrate synthase. 14d and 14e were designed to mimic the tetrahedral intermediate or transition state in the reaction of chloramphenicol acetyltransferase and related acetyl-CoA-dependent acetyltransferases. Both compounds are poor inhibitors of chloramphenicol acetyltransferase, with affinities slightly lower than that of acetyl-CoA, indicating that these compounds are not good mimics of the enzyme-bound tetrahedral intermediate or transition state.

  DOI：

  10.1021/ja00090a014
• 作为产物：
  描述：

  sodium pantothenate 、 对甲苯磺酸甲酯 以 甲醇 为溶剂， 生成 (R)-N-(2,4-二羟基-3,3-二甲基-1-氧代丁基)-beta-丙氨酸甲酯
  参考文献：
  名称：

  Synthesis of Novel Analogs of Acetyl Coenzyme A: Mimics of Enzyme Reaction Intermediates

  摘要：

  An improved method for the synthesis of analogs of coenzyme A (CoA) and its thioesters, which are modified in the thiol or thioester moiety, has been developed using a combination of chemical and enzymatic reactions, The enzymes catalyzing the last two steps of CoA biosynthesis were used to prepare a CoA analog (1c) in which an amide bond is replaced by a thioester bond and the thiol group is replaced by a methyl group. Reaction of 1c with a primary amine in aqueous solution results in aminolysis of the thioester linkage to form the desired CoA analog. Reaction with different amines permits the introduction of a variety of functional groups in place of the nor mal thiol or thioester group. This methodology has been used in the synthesis of five new analogs of acetyl-CoA in which the thioester sulfur is replaced by a methylene group and the acetyl group is replaced by carboxylate (14a), nitro (14b), carboxamide (14c), methyl sulfoxide (14d), and methyl sulfone (14e) groups. 14a-c were designed to mimic the possible enolate or enol intermediate in the reaction of citrate synthase and related enzymes. 14a and 14c are potent inhibitors of citrate synthase, with K-i values 1000- and 570-fold lower than the K-m for acetyl-CoA, respectively. CD titrations indicate that 14a and 14c have low affinity for citrate synthase in the absence of oxaloacetate, consistent with their recognition as enol or enolate analogs. 14b is a poor inhibitor of citrate synthase, with affinity slightly lower than that for acetyl-CoA. These results are consistent with generation of the enol form of acetyl-CoA as the nucleophilic intermediate in the reaction of citrate synthase. 14d and 14e were designed to mimic the tetrahedral intermediate or transition state in the reaction of chloramphenicol acetyltransferase and related acetyl-CoA-dependent acetyltransferases. Both compounds are poor inhibitors of chloramphenicol acetyltransferase, with affinities slightly lower than that of acetyl-CoA, indicating that these compounds are not good mimics of the enzyme-bound tetrahedral intermediate or transition state.

  DOI：

  10.1021/ja00090a014

文献信息

• [EN] CYCLIC PHOSPHATES AND CYCLIC PHOSPHORAMIDATES FOR THE TREATMENT OF NEUROLOGIC DISORDERS<br/>[FR] PHOSPHATES CYCLIQUES ET PHOSPHORAMIDATES CYCLIQUES POUR LE TRAITEMENT DE TROUBLES NEUROLOGIQUES
  申请人：RETROPHIN INC

  公开号：WO2017099822A1

  公开（公告）日：2017-06-15

  Compounds having the following formula (I): and pharmaceutically acceptable salts thereof, wherein A, B, D, E and R1 are as defined herein, are provided. Methods comprising the use of such compounds for the treatment of neurological disorders, such as pantothenate kinase-associated neurodegeneration, and pharmaceutical compositions containing such compounds, and their use in the treatment of neurological disorders, also are provided.

  提供具有以下化学式（I）的化合物及其药用可接受的盐，其中A、B、D、E和R1的定义如本文所述。提供了使用这些化合物治疗神经系统疾病（如泛酸激酶相关性神经退行性疾病）的方法，以及含有这些化合物的药物组合物，以及它们在治疗神经系统疾病中的用途。
• Probing the ligand preferences of the three types of bacterial pantothenate kinase
  作者：Jinming Guan、Leanne Barnard、Jeanne Cresson、Annabelle Hoegl、Justin H. Chang、Erick Strauss、Karine Auclair

  DOI：10.1016/j.bmc.2018.10.042

  日期：2018.12

  Pantothenate kinase (PanK) catalyzes the transformation of pantothenate to 4′-phosphopantothenate, the first committed step in coenzyme A biosynthesis. While numerous pantothenate antimetabolites and PanK inhibitors have been reported for bacterial type I and type II PanKs, only a few weak inhibitors are known for bacterial type III PanK enzymes. Here, a series of pantothenate analogues were synthesized

  泛酸激酶（PanK）催化泛酸向4'-磷酸泛酸的转化，这是辅酶A生物合成的第一步。尽管已经报道了多种泛酸抗代谢物和PanK抑制剂可用于细菌I型和II型PanK，但只有少数弱抑制剂可用于细菌III型PanK酶。在这里，使用方便的合成方法合成了一系列泛酸类似物。将该化合物用作小型有机探针，以比较三种不同类型细菌PanK的配体偏好。总体而言，每种PanK类型都鉴定了几种新的抑制剂和底物。
• Cyclic Phosphopantothenic Acid Prodrugs for Treatment of Pantothenate Kinase-Associated Neurodegeneration
  作者：Giulio Auciello、Annalise Di Marco、Odalys Gonzalez Paz、Savina Malancona、Steven Harper、Maria Beconi、Ilaria Rossetti、Alina Ciammaichella、Paola Fezzardi、Andrea Vecchi、Elena Bracacel、Daniel Cicero、Edith Monteagudo、Daniel Elbaum

  DOI：10.1021/acs.jmedchem.0c01531

  日期：2020.12.24

  low levels of coenzyme-A (CoA) in the CNS due to impaired production of phosphopantothenic acid (PPA) from vitamin B5. Restoration of central PPA levels by delivery of exogenous PPA is a recent strategy to reactivate CoA biosynthesis in PKAN patients. Fosmetpantotenate is an oral PPA prodrug. We report here the development of a new PANk2–/– knockout model that allows CoA regeneration in brain cells

  人类PANK2基因的突变与神经退行性疾病（如泛酸激酶相关的神经退行性疾病（PKAN））有关，由于维生素B5的磷酸泛酸（PPA）的生产受损，导致CNS中的辅酶A（CoA）含量较低。通过递送外源PPA恢复中枢PPA水平是重新激活PKAN患者CoA生物合成的最新策略。泛泛酸磷酯为口服PPA前药。我们在这里报告新PANk2的开发– / –可以评估脑细胞中CoA再生的基因剔除模型，并描述了两个新系列的PPA环状磷酸酯前药，能够在该系统中再生优异水平的CoA。在小鼠中进行的概念验证研究证明，这类新型前药在口服后可将PPA递送至大脑，并证实将前药衍生的PPA纳入CoA。
• PANTOTHENATE DERIVATIVES FOR THE TREATMENT OF NEUROLOGIC DISORDERS
  申请人：RETROPHIN, INC.

  公开号：US20130289001A1

  公开（公告）日：2013-10-31

  The present disclosure relates to pantothenate derivatives for the treatment of neurologic disorders (such as pantothenate kinase-associated neurodegeneration), pharmaceutical compositions containing such compounds, and their use in treatment of neurologic disorders.

  本公开涉及泛酸衍生物用于治疗神经系统疾病（如泛酸激酶相关性神经退行性疾病），含有这些化合物的药物组合物，以及它们在神经系统疾病治疗中的应用。
• [EN] PANOTHENATE DERIVATIVES FOR THE TREATMENT OF NEUROLOGICAL DISORDERS<br/>[FR] DÉRIVÉS PANOTHÉNATE POUR LE TRAITEMENT DE TROUBLES NEUROLOGIQUES
  申请人：RETROPHIN INC

  公开号：WO2015061792A1

  公开（公告）日：2015-04-30

  Compounds having the following formula (E): Formula E or a pharmaceutically acceptable salt thereof, wherein R, R', R'', X and n are as defined herein are provided. Methods comprising use of such compounds for the treatment of neurologic disorders, such as pantothenate kinase-associated neurodegeneration, and pharmaceutical compositions containing such compounds, and their use in treatment of neurologic disorders are also provided.

  提供具有以下公式（E）的化合物：公式E或其药学上可接受的盐，其中R、R'、R''、X和n如本文所定义。还提供了使用这些化合物治疗神经系统疾病（如泛酸激酶相关性神经退行性疾病）的方法，以及含有这些化合物的药物组合物，以及它们在治疗神经系统疾病中的应用。