H-Nva-Pro-NH2 | 127896-84-8

• 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: H-Nva-Pro-NH2
• 英文别名: L-norvalyl-L-prolinamide；(2S)-1-[(2S)-2-aminopentanoyl]pyrrolidine-2-carboxamide
• CAS: 127896-84-8
• 化学式: C₁₀H₁₉N₃O₂
• 分子量: 213.28
• InChiKey: NOBVHVGPMMOHAE-YUMQZZPRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.6
• 重原子数：
  15
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  89.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  H-Nva-Pro-NH2 在 N-甲基吗啉 、 TFA-anisole 、 氯甲酸异丁酯 作用下， 反应 1.75h， 生成 (S)-2-Amino-pentanedioic acid 5-amide 1-{[(S)-1-((S)-2-carbamoyl-pyrrolidine-1-carbonyl)-butyl]-amide}
  参考文献：
  名称：

  Synthesis of thyrotropin-releasing hormone-related peptides using N.ALPHA.-tert-dutyflxycarbonyl-.OMEGA.-(N-tert-butyloxycarbonylcarbamoyl)-.ALPHA.-amino acids.

  摘要：

  研究人员研究了 Nα，Nca-二叔丁氧羰基高谷氨酰胺在合成促甲状腺激素释放激素（TRH）类似物中的应用。在含有乙酸的水或二氧六环中，均谷氨酰胺肽形成δ-内酰胺比谷氨酰胺肽形成γ-内酰胺更容易。[pHgu1，Nva2]-TRH 对小鼠戊巴比妥麻醉具有剂量依赖性拮抗活性，但对大鼠脑中的 TRH 受体几乎没有结合活性。

  DOI：

  10.1248/cpb.37.3125
• 作为产物：
  描述：

  Z-L-正缬氨酸 在 palladium on activated charcoal N-乙基吗啉 、 氢气 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 20.0~25.0 ℃ 、206.84 kPa 条件下， 反应 3.5h， 生成 H-Nva-Pro-NH2
  参考文献：
  名称：

  Inhibitors of Tripeptidyl Peptidase II. 3. Derivation of Butabindide by Successive Structure Optimizations Leading to a Potential General Approach to Designing Exopeptidase Inhibitors

  摘要：

  The cholecystokinin-8 (CCK-8)-inactivating peptidase is a serine peptidase that has been shown to be a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10). It cleaves the neurotransmitter CCK-8 sulfate at the Met-Gly bond to give Asp-Tyr(SO(3)H)-Met-OH + GlyTrp-Met-Asp-Phe-NH(2). Starting from Val-Pro-NHBu, a dipeptide of submicromolar affinity that had previously been generated to serve as a lead, successive optimization at P3, P1, and then P2 gave Abu-Pro-NHBu (18, K(i) = 80 nM). Further transformation (by making a benzologue) gave the indoline analogue, butabindide (33) as a reversible inhibitor having nanomolar affinity (Ki = 7 nM). Retrospective analysis suggested the possibility of a general approach to designing exopeptidase inhibitors starting from the structure of the first hydrolysis product. Application of this approach to CCK-8 led to Abu-Phe-NHBu (37), but this only had K(i) = 9.4 mu M. Molecular modeling, to determine the minimum energy conformations and explain the 1000-fold better affinity of butabindide, indicated that 37 cannot access the likely active conformation of butabindide.

  DOI：

  10.1021/jm0500830

文献信息

• Synthesis of thyrotropin-releasing hormone analogs. 2. Tripeptides structurally greatly different from TRH with high central nervous system activity
  作者：Tamas Szirtes、Lajos Kisfaludy、Eva Palosi、Laszlo Szporny

  DOI：10.1021/jm00159a015

  日期：1986.9

  from TRH. In spite of this fact, 7 of the 17 analogues (1, 2, 8-10, 16, and 17) have stronger anticataleptic effect than TRH, with negligible or no hormonal potency. The highest CNS activity was achieved when pyroglutamic acid was replaced by pyro-2-aminoadipic acid at the N-terminus [pAad-Leu-Pro-NH2, 1 (RGH 2202), and pAad-Nva-Pro-NH2,2]. A novel synthesis of L-2-aminoadipic acid suitable for large-scale

  通过五氟苯基酯法合成了一系列新的促甲状腺激素释放激素（TRH）类似物，这些类似物是通过进一步修饰我们最有效的中枢神经系统（CNS）在两个末端刺激中性三肽而获得的，并测试了CNS和促甲状腺激素（TSH）释放活动。[Leu2]中的吡咯-2-氨基己二酸，2-氧代咪唑烷-4-羧酸或γ-丁内酯-γ-羧酸取代脯氨酸谷氨酸，脯氨酸由哌啶酸，噻唑烷-4-羧酸或高脯氨酸代替脯氨酸。 -和[Nva2] TRH导致三肽结构上与TRH大不相同。尽管如此，17种类似物中的7种（1、2、8-10、16和17）比TRH具有更强的抗感性作用，激素作用微乎其微或无。当焦谷氨酸在N端被焦-2-氨基己二酸取代时，CNS活性最高[pAad-Leu-Pro-NH2，1（RGH 2202）和pAad-Nva-Pro-NH2,2]。还描述了适用于大规模制备的L-2-氨基己二酸的新颖合成。
• Tripeptides acting on the central nervous system and a process for the
  申请人：Patentbureau DANUBIA

  公开号：US04386073A1

  公开（公告）日：1983-05-31

  The invention relates to new peptide derivatives which act on the central nervous system and correspond to the general formula (I), X--Y--W--NH.sub.2 (I) wherein X is L-pyroglutamyl, D-pyroglutamyl, L-2-keto-imidazolidine-4-carbonyl, L-6-keto-pipecolyl, L-thiazolidine-4-carbonyl, L-prolyl or orotyl group, Y is L-leucyl, L-norvalyl or L-histidyl group, and W is L-prolyl, D-prolyl, L-thiazolidine-4-carbonyl, L-pipecolyl, L-homoprolyl, L-leucyl, L-isoleucyl, L-methionyl or D-pipecolyl group, or the W-NH.sub.2 group stands for pyrrolidyl or piperidyl group, with the proviso that if X is L-pyroglutamyl and Y is L-histidyl group, W is other than L-prolyl group, and pharmaceutically acceptable complexes thereof. These compounds are prepared by methods commonly applied in the peptide chemistry.

  本发明涉及一种新的肽衍生物，其作用于中枢神经系统，符合通式（I），X-Y-W-NH.sub.2（I），其中X为L-吡咯糜酰基，D-吡咯糜酰基，L-2-酮咪唑啉-4-羧酰基，L-6-酮-哌嗪基，L-噻唑啉-4-羧酰基，L-脯氨酰基或乌洛替基，Y为L-亮氨酰基，L-异戊氨酰基或L-组氨酰基，W为L-脯氨酰基，D-脯氨酰基，L-噻唑啉-4-羧酰基，L-哌嗪基，L-同型脯氨酰基，L-亮氨酰基，L-异亮氨酰基，L-甲硫氨酰基或D-哌嗪基，或W-NH.sub.2基团代表吡咯烷基或哌啶基，但如果X为L-吡咯糜酰基且Y为L-组氨酰基，则W为除L-脯氨酰基以外的其他基团，以及其药学上可接受的复合物。这些化合物是通过肽化学中常用的方法制备的。
• SAKURA, NAOKI;HIROSE, KYOKO;NISHIJIMA, NIWAKO;HASHIMOTO, TADASHI;OKABE, T+, CHEM. AND PHARM. BULL., 37,(1989) N1, C. 3125-3127
  作者：SAKURA, NAOKI、HIROSE, KYOKO、NISHIJIMA, NIWAKO、HASHIMOTO, TADASHI、OKABE, T+

  DOI：——

  日期：——
• SUZUKI, MAMORU;GUGANO, HIROSHI;MATSUMOTO, KAZUO;YAMAMURA, MICHIO;ISHIDA, +, J. MED. CHEM., 33,(1990) N, C. 2130-2137
  作者：SUZUKI, MAMORU、GUGANO, HIROSHI、MATSUMOTO, KAZUO、YAMAMURA, MICHIO、ISHIDA, +

  DOI：——

  日期：——
• Inhibitors of Tripeptidyl Peptidase II. 3. Derivation of Butabindide by Successive Structure Optimizations Leading to a Potential General Approach to Designing Exopeptidase Inhibitors
  作者：C. Robin Ganellin、Paul B. Bishop、Ramesh B. Bambal、Suzanne M. T. Chan、Bertrand Leblond、Andrew N. J. Moore、Lihua Zhao、Pierre Bourgeat、Christiane Rose、Froylan Vargas、Jean-Charles Schwartz

  DOI：10.1021/jm0500830

  日期：2005.11.1

  The cholecystokinin-8 (CCK-8)-inactivating peptidase is a serine peptidase that has been shown to be a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10). It cleaves the neurotransmitter CCK-8 sulfate at the Met-Gly bond to give Asp-Tyr(SO(3)H)-Met-OH + GlyTrp-Met-Asp-Phe-NH(2). Starting from Val-Pro-NHBu, a dipeptide of submicromolar affinity that had previously been generated to serve as a lead, successive optimization at P3, P1, and then P2 gave Abu-Pro-NHBu (18, K(i) = 80 nM). Further transformation (by making a benzologue) gave the indoline analogue, butabindide (33) as a reversible inhibitor having nanomolar affinity (Ki = 7 nM). Retrospective analysis suggested the possibility of a general approach to designing exopeptidase inhibitors starting from the structure of the first hydrolysis product. Application of this approach to CCK-8 led to Abu-Phe-NHBu (37), but this only had K(i) = 9.4 mu M. Molecular modeling, to determine the minimum energy conformations and explain the 1000-fold better affinity of butabindide, indicated that 37 cannot access the likely active conformation of butabindide.