4-((S)-2-((4-(4-氯苯氧基)苯氧基)甲基)吡咯烷-1-基)丁酸盐酸盐 | 929915-58-2

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 4-((S)-2-((4-(4-氯苯氧基)苯氧基)甲基)吡咯烷-1-基)丁酸盐酸盐
• 中文别名: 4 - ((S)-2 - ((4-(4-氯苯氧基)苯氧基)甲基)吡咯烷-1-基)丁酸盐酸盐
• 英文名称: 4-{(S)-2-(4-(4-chlorophenoxy)phenoxymethyl)pyrrolidin-1-yl}-1-butyric acid hydrochloride
• 英文别名: 4-{(2S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidin-1-yl}butyric acid hydrochloride；DG-051；4-{(S)-2-[4-(4-Chloro-phenoxy)-phenoxymethyl]-pyrrolidin-1-yl}-butyric acid hydrochloride；4-{(S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidin-1-yl}butyric acid hydrochloride；4-((S)-2-((4-(4-chlorophenoxy)phenoxy)Methyl)pyrrolidin-1-yl)butanoic acid hydrochloride；4-[(2S)-2-[[4-(4-chlorophenoxy)phenoxy]methyl]pyrrolidin-1-yl]butanoic acid;hydrochloride
• CAS: 929915-58-2
• 化学式: C₂₁H₂₄ClNO₄*ClH
• 分子量: 426.34
• InChiKey: UCPVOTSNNAVKNE-LMOVPXPDSA-N

物化性质

• 溶解度：
  DMF：20mg/mL； DMSO：12.5mg/mL；乙醇：12.5mg/mL； PBS（pH 7.2）：2 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  5.26
• 重原子数：
  28
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  59
• 氢给体数：
  2
• 氢受体数：
  5

安全信息

• 储存条件：
  2-8℃

制备方法与用途

DG051是一种有效的白三烯A4水解酶抑制剂，其IC50值为47纳摩尔。

反应信息

• 作为反应物：
  描述：

  4-((S)-2-((4-(4-氯苯氧基)苯氧基)甲基)吡咯烷-1-基)丁酸盐酸盐 在 sodium hydroxide 作用下， 以 水 为溶剂， 以84.5%的产率得到(S)-4-(2-((4-(4-氯苯氧基)苯氧基)甲基)吡咯烷-1-基)丁酸
  参考文献：
  名称：

  Development of a Scalable Synthetic Process for DG-051B, A First-in-Class Inhibitior of LTA4H

  摘要：

  DG-051B is a first-in-class small molecule inhibitor of leukotriene A4 hydrolase (LTA4H), currently in Phase H clinical development for the prevention of heart attack. Process optimization led from a linear seven-step synthetic procedure to a convergent four-step manufacturing sequence that has been used to manufacture at 100-kg scale. The entire process can be telescoped due to high conversion reactions, low impurity levels, efficient separations, and a very effective final purification. Two key aspects of the process are: (a) bypassing the isolation of a reactive electrophile by using its aqueous-washed reaction mixture directly into a coupling reaction with a phenoxide nucleophile and (b) modulating the properties of the final product solutions for optimal extraction, purification, and crystallization.

  DOI：

  10.1021/op900231j
• 作为产物：
  描述：

  (S)-4-(2-((4-(4-氯苯氧基)苯氧基)甲基)吡咯烷-1-基)丁酸 在 盐酸 作用下， 以 乙醚 为溶剂， 反应 2.0h， 生成 4-((S)-2-((4-(4-氯苯氧基)苯氧基)甲基)吡咯烷-1-基)丁酸盐酸盐
  参考文献：
  名称：

  BIARYL SUBSTITUTED HETEROCYCLE INHIBITORS OF LTA4H FOR TREATING INFLAMMATION

  摘要：

  这项发明涉及一种化学类别的双芳基取代杂环抑制剂，用于治疗、预防和预防炎症性疾病和紊乱。这些化合物具有一般公式Ψ：一个例子是

  公开号：

  US20070066820A1

文献信息

• [EN] PROCESS FOR PREPARING 4- { (S) -2- (4-(4-CHLOROPHENOXY) PHENOXYMETHYL) PYRROLIDIN-1-YL) } BUTYRIC ACID AND SALTS THEREOF<br/>[FR] PROCÉDÉ DE PRÉPARATION DE L'ACIDE 4-{(S)-2-(4-(4-CHLOROPHÉNOXY)PHÉNOXYMÉTHYL)PYRROLIDIN-1-YL}BUTYRIQUE ET DE SES SELS
  申请人：DECODE GENETICS EHF

  公开号：WO2011011598A1

  公开（公告）日：2011-01-27

  The present invention relates to a process for preparing 4-(S)-2-[4-(4-chlorophenoxy)phenoxymethyl]pyrrolidin-1-yl}butyric acid and its salts.

  本发明涉及一种制备4-(S)-2-[4-(4-氯苯氧基)苯氧甲基]吡咯烷-1-基}丁酸及其盐的方法。
• Synthesis and structural assignment of two major metabolites of the LTA4H inhibitor DG-051
  作者：Livia A. Enache、Jun Zhang、David W. Sullins、Isaac Kennedy、Emmanuel Onua、David E. Zembower、Frank W. Muellner、Jasbir Singh、Alex S. Kiselyov

  DOI：10.1016/j.bmcl.2009.09.097

  日期：2009.11

  The same two major CYP mediated metabolites of DG-051 were produced in the presence of rat, dog, monkey and human liver microsomes. Their respective structures were hypothesized based on mass spectrometry data correlated with the parent structure and confirmed by comparison with authentic synthetic samples. The number of regioisomers synthesized as candidates for metabolite M1 was narrowed down using

  在大鼠，狗，猴和人肝微粒体的存在下，产生了相同的两种主要的CYP介导的DG-051代谢产物。根据与母体结构相关的质谱数据假设其各自的结构，并通过与真实的合成样品进行比较进行确认。使用选择性氘化的DG-051类似物的代谢研究，可以缩小合成为代谢物M1候选物的区域异构体的数量。
• Biaryl substituted heterocycle inhibitors of LTA4H for treating inflammation
  申请人：deCODE genectics ehf.

  公开号：US07402684B2

  公开（公告）日：2008-07-22

  The present invention relates to a chemical genus of biaryl substituted heterocycle inhibitors of LTA4H (leukotriene A4 hydrolase) useful for the treatment and prevention and prophylaxis of inflammatory diseases and disorders. The compounds have general formula Ψ: An example is

  本发明涉及一种化学种类的双芳基取代杂环抑制剂LTA4H（白三烯A4水解酶），可用于治疗、预防和预防炎症性疾病和疾病。该化合物具有一般式Ψ：一个例子是
• Discovery of 4-[(2<i>S</i>)-2-{[4-(4-Chlorophenoxy)phenoxy]methyl}-1-pyrrolidinyl]butanoic Acid (DG-051) as a Novel Leukotriene A4 Hydrolase Inhibitor of Leukotriene B4 Biosynthesis
  作者：Vincent Sandanayaka、Bjorn Mamat、Rama K. Mishra、Jennifer Winger、Michael Krohn、Li-Ming Zhou、Monica Keyvan、Livia Enache、David Sullins、Emmanuel Onua、Jun Zhang、Gudrun Halldorsdottir、Heida Sigthorsdottir、Audur Thorlaksdottir、Gudmundur Sigthorsson、Margret Thorsteinnsdottir、Douglas R. Davies、Lance J. Stewart、David E. Zembower、Thorkell Andresson、Alex S. Kiselyov、Jasbir Singh、Mark E. Gurney

  DOI：10.1021/jm900838g

  日期：2010.1.28

  Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA(4)H) as a key target for the treatment of cardiovascular disease. We combined fragment-based crystallography screening with an iterative medicinal chemistry effort to optimize inhibitors of LTA(4)H. Ligand efficiency was followed throughout our structure-activity studies. As applied within the context of LTA(4)H inhibitor design, the chemistry team was able to design a potent compound 20 (DG-051) (K(d) = 26 nM) with high aqueous solubility (>30 mg/mL) and high oral bioavailability (>80% across species) that is currently undergoing clinical evaluation for the treatment of myocardial infarction and stroke. The structural biology-chemistry interaction described in this paper provides a sound alternative to conventional screening techniques. This is the first example of a gene-to-clinic paradigm enabled by a fragment-based drug discovery effort.
• Org. Process Res. Dev. 2009, 13, 1177-1184
  作者：

  DOI：——

  日期：——