(S)-2-[(Pyridine-3-carbonyl)-amino]-propionic acid tert-butyl ester | 70643-33-3

• 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: (S)-2-[(Pyridine-3-carbonyl)-amino]-propionic acid tert-butyl ester
• 英文别名: Nicotinoyl-alanine t-butyl ester；tert-butyl (2S)-2-(pyridine-3-carbonylamino)propanoate
• CAS: 70643-33-3
• 化学式: C₁₃H₁₈N₂O₃
• 分子量: 250.298
• InChiKey: SOAXESQKGCGLAI-VIFPVBQESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  18
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  68.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (S)-2-[(Pyridine-3-carbonyl)-amino]-propionic acid tert-butyl ester 在 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 乙酸乙酯 为溶剂， 反应 2.5h， 生成 (2,3,4,5,6-pentafluorophenyl) (2S)-2-(pyridine-3-carbonylamino)propanoate
  参考文献：
  名称：

  Brain-Targeted Delivery of a Leucine-enkephalin Analogue by Retrometabolic Design

  摘要：

  A brain-targeted chemical delivery system (CDS) based on retrometabolic drug design was applied to a Leu-enkephalin analogue, Tyr-D-Ala-Gly-Phe-D-Leu (DADLE). The molecular architecture of the peptide CDS disguises its peptide nature from neuropeptide-degrading enzymes and provides lipophilic, bioreversible functions for the penetration through the blood-brain barrier. These functions were provided by a targetor, a 1,4-dihydrotrigonellyl group, on the N-terminus and a bulky, lipophilic ester group on the C-terminus. A spacer amino acid residue was also inserted between the targetor and the parent peptide to assure the release of DADLE by specific enzymes. Four CDSs were synthesized by segment-coupling method that proved to be superior to sequential elongation in obtaining this type of peptide conjugates. Intravenous injection of the compounds produced a significant and long-lasting response in rats monitored by the tail-flick latency measurements. CDSs having the bulkier cholesteryl group showed a better efficacy than those having the smaller 1-adamantaneethyl ester. The spacer was the most important factor to manipulate the rate of DADLE release and, thus, the pharmacological activity; proline as a spacer produced more potent analgesia than alanine. The antinociceptive effect of the CDSs was naloxone-reversible and methylnaloxonium-irreversible, confirming that central opiate receptors were solely responsible for mediating analgesia induced by the peptide CDS that delivered, retained, and then released the peptide in the brain.

  DOI：

  10.1021/jm960356e
• 作为产物：
  描述：

  L-丙氨酸叔丁酯盐酸盐 、 氯化烟碱盐酸盐 在 TEA 作用下， 以 二氯甲烷 为溶剂， 生成 (S)-2-[(Pyridine-3-carbonyl)-amino]-propionic acid tert-butyl ester
  参考文献：
  名称：

  Brain-Targeted Delivery of a Leucine-enkephalin Analogue by Retrometabolic Design

  摘要：

  A brain-targeted chemical delivery system (CDS) based on retrometabolic drug design was applied to a Leu-enkephalin analogue, Tyr-D-Ala-Gly-Phe-D-Leu (DADLE). The molecular architecture of the peptide CDS disguises its peptide nature from neuropeptide-degrading enzymes and provides lipophilic, bioreversible functions for the penetration through the blood-brain barrier. These functions were provided by a targetor, a 1,4-dihydrotrigonellyl group, on the N-terminus and a bulky, lipophilic ester group on the C-terminus. A spacer amino acid residue was also inserted between the targetor and the parent peptide to assure the release of DADLE by specific enzymes. Four CDSs were synthesized by segment-coupling method that proved to be superior to sequential elongation in obtaining this type of peptide conjugates. Intravenous injection of the compounds produced a significant and long-lasting response in rats monitored by the tail-flick latency measurements. CDSs having the bulkier cholesteryl group showed a better efficacy than those having the smaller 1-adamantaneethyl ester. The spacer was the most important factor to manipulate the rate of DADLE release and, thus, the pharmacological activity; proline as a spacer produced more potent analgesia than alanine. The antinociceptive effect of the CDSs was naloxone-reversible and methylnaloxonium-irreversible, confirming that central opiate receptors were solely responsible for mediating analgesia induced by the peptide CDS that delivered, retained, and then released the peptide in the brain.

  DOI：

  10.1021/jm960356e

文献信息

• Brain-enhanced delivery of neuroactive peptides by sequential metabolism
  申请人：University of Florida

  公开号：US05624894A1

  公开（公告）日：1997-04-29

  The invention provides novel peptide derivatives which are designed to deliver pharmacologically active peptides into the central nervous system by sequential metabolism. The peptide is placed in a molecular environment which disguises its peptide nature and provides biolabile, lipophilic functions to penetrate the blood-brain barrier by passive transport. The design incorporates a dihydropyridine-type redox targetor moiety, an amino acid or di- or -tripeptide spacer inserted between the targetor and N-terminal amino acid unit of the peptide and a bulky, lipophilic substituent protecting the C-terminal amino acid unit of the peptide. The dihydropyridine-type targetor undergoes an enzymatically mediated oxidation to a hydrophilic, membrane-impermeable pyridinium salt. That polar targetor-peptide conjugate is trapped behind the lipoidal blood-brain barrier. Over time, cleavage of the lipophilic ester from the peptide by esterase and or lipase enzymes and enzymatic cleavage of the targetor-spacer from the peptide results in release of the desired peptide in the brain.

  本发明提供了新型肽衍生物，旨在通过顺序代谢将药理活性肽递送到中枢神经系统。该肽置于分子环境中，掩盖其肽性质，并提供生物可降解、亲脂性功能以通过被动转运穿透血脑屏障。该设计包括一种二氢吡啶型氧化还原靶标基团、插入在靶标基团和肽的N-末端氨基酸单元之间的氨基酸或二肽/三肽间隔子，以及保护肽的C-末端氨基酸单元的笨重、亲脂性取代基。二氢吡啶型靶标基团经过酶介导的氧化作用，转化为亲水性、膜不透性的吡啶盐。这种极性的靶标-肽共轭物被困在脂质型血脑屏障后。随着时间的推移，酯酶和/或脂肪酶酶解肽中的亲脂性酯基团和靶标-间隔子，导致所需的肽在大脑中释放。
• BRAIN-ENHANCED DELIVERY OF NEUROACTIVE PEPTIDES BY SEQUENTIAL METABOLISM
  申请人：UNIVERSITY OF FLORIDA

  公开号：EP0661986A1

  公开（公告）日：1995-07-12
• EP0661986A4
  申请人：——

  公开号：EP0661986A4

  公开（公告）日：1997-04-23
• US5624894A
  申请人：——

  公开号：US5624894A

  公开（公告）日：1997-04-29
• [EN] BRAIN-ENHANCED DELIVERY OF NEUROACTIVE PEPTIDES BY SEQUENTIAL METABOLISM<br/>[FR] APPORT STIMULE PAR LE CERVEAU DE PEPTIDES NEUROACTIFS PAR METABOLISME SEQUENTIEL
  申请人：UNIVERSTIY OF FLORIDA

  公开号：WO1994006450A1

  公开（公告）日：1994-03-31

  (EN) The invention provides novel peptide derivatives which are designed to deliver pharmacologically active peptides into the central nervous system by sequential metabolism. The peptide is placed in a molecular environment which disguises its peptide nature and provides biolabile, lipophilic functions to penetrate the blood-brain barrier by passive transport. The design incorporates a dihydropyridine-type redox targetor moiety, an amino acid or di- or tripeptide spacer inserted between the targetor and N-terminal amino acid unit of the peptide and a bulky, lipophilic substituent protecting the C-terminal amino acid unit of the peptide. The dihydropyridine-type targetor undergoes an enzymatically mediated oxidation to a hydrophilic, membrane-impermeable pyridinium salt. That polar targetor-peptide conjugate is trapped behind the lipoidal blood-brain barrier. Over time, cleavage of the lipophilic ester from the peptide by esterase and/or lipase enzymes and enzymatic cleavage of the targetor-spacer from the peptide results in release of the desired peptide in the brain.(FR) L'invention concerne de nouveaux dérivés de peptides conçus pour apporter des peptides pharmacologiquement actifs au système nerveux central par métabolisme séquentiel. On place le peptide dans un environnement moléculaire qui déguise sa nature peptidique et offre des fonctions biolabiles lipophiles pour pénétrer la barrière hématoencéphalique par transport passif. La conception incorpore une fraction de ciblage d'oxydo-réduction de type dihydropyridine, un acide aminé ou un espaceur di- ou tripeptidique inséré entre la fraction de ciblage et l'unité d'acide aminé N-terminal du peptide, ainsi qu'un substituant volumineux lipophile protégeant l'unité d'acide aminé C-terminal du peptide. La fraction de ciblage de type dihydropyridine subit une oxydation induite par voie enzymatique en un sel hydrophile de pyridinium imperméable à la membrane. Ce conjugué fraction de ciblage-peptide polaire est piégé derrière la barrière hématoencéphalique lipoïdique. Au fil du temps, le clivage de l'ester lipophile à partir du peptide par l'estérase et/ou la lipase ainsi que le clivage enzymatique de la fraction de ciblage/espaceur à partir du peptide ont pour résultat la libération du peptide voulu dans le cerveau.