(S)-3-Phenyl-2-(3-pyridin-3-yl-propionylamino)-propionic acid | 139522-04-6

• 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)-3-Phenyl-2-(3-pyridin-3-yl-propionylamino)-propionic acid
• 英文别名: (2S)-3-phenyl-2-(3-pyridin-3-ylpropanoylamino)propanoic acid
• CAS: 139522-04-6
• 化学式: C₁₇H₁₈N₂O₃
• 分子量: 298.342
• InChiKey: KTYJSGFOKJRZID-HNNXBMFYSA-N

物化性质

• 沸点：
  585.5±50.0 °C(Predicted)
• 密度：
  1.227±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  79.3
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (S)-3-Phenyl-2-(3-pyridin-3-yl-propionylamino)-propionic acid 、 在 1-羟基苯并三唑 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 N-<1-oxo-3-(3-pyridinyl)propyl>-L-phenylalanyl-N-<1(S)-(cyclohexylmethyl)-3,3-difluoro-2(R)-hydroxy-4-<<2-(4-morpholinyl)ethyl>amino>-4-oxobutyl>-4,5-didehydro-L-norvalinamide
  参考文献：
  名称：

  Design and synthesis of potent, selective, and orally active fluorine-containing renin inhibitors

  摘要：

  A series of primate renin inhibitors containing difluorocarbinol and difluoroketone groups at the P1-P1' position have been synthesized and studied both in vitro and in vivo. In vitro, the compounds were evaluated as inhibitors of monkey renin and the closely related aspartic proteinase, cathepsin D (bovine), as a measure of enzyme selectivity. Interestingly, the difluoroketone derivatives showed greatly reduced selectivity compared with the corresponding alcohols. However, selectivity could be enhanced by judicious choice of other substituents. Sites influencing selectivity, included not only P2, Which is well-known to strongly affect selectivity, but also the P4, P1-P1', and P2' sites. These results make possible the design of inhibitors with a greater selectivity for either renin versus cathepsin D. In vivo several of the compounds in the difluoroketone series have shown good oral activity in the salt depleted normotensive cynomolgus monkey model.

  DOI：

  10.1021/jm00079a001

文献信息

• Novel Renin Inhibitors Containing (2S,3S,5S)-2-Amino-1-cyclohexyl-6-methyl-3,5-heptanediol Fragment as a Transition-state Mimic at the P1-P1' Cleavage Site.
  作者：Yasuki YAMADA、Koji ANDO、Yukishige IKEMOTO、Hiroki TADA、Eiji SHIRAKAWA、Eiji INAGAKI、Saizo SHIBATA、Ikuro NAKAMURA、Yoshiharu HAYASHI、Kiyoteru IKEGAMI、Itsuo UCHIDA

  DOI：10.1248/cpb.45.1631

  日期：——

  A series of renin inhibitors containing the (2S, 3S, 5S)-2-amino-1-cyclohexyl-6-methyl-3, 5-heptanediol (2-amino-3, 5-anti-diol) fragment as a novel transition-state mimic was synthesized, and their biological activities were evaluated. All of the synthesized compounds containing the 2-amino-3, 5-anti-diol fragment at the P1-P1' position showed high in vitro renin-inhibitory activity with IC50 values in the 10-8-10-10M range, and most of them caused a reduction of blood pressure when administered orally to salt-depleted, conscious marmosets. The inhibitor (29) with the 4-hydroxypiperidine residue at the P4 position showed the highest activity in terms of both potency and duration of the blood pressure-lowering effect.

  合成了一系列含有(2S, 3S, 5S)-2-氨基-1-环己基-6-甲基-3, 5-庚二醇（2-氨基-3, 5-反-二醇）片段作为新型过渡态模拟物的新型肾素抑制剂，并评价了它们的生物活性。所有在P1-P1'位置含有2-氨基-3, 5-反-二醇片段的合成化合物均表现出高体外肾素抑制活性，IC50值在10-8至10-10M范围内，并且大多数化合物在口服给盐缺乏的清醒狨猴时能降低血压。在P4位置含有4-羟基哌啶残基的抑制剂（29）在降低血压作用的强度和持续时间方面表现出最高的活性。
• NOVEL 4-SUBSTITUTED-3-PEPTIDYL-AZETIDIN-2-ONE DERIVATIVES USEFUL AS CYSTEINE PROTEINASE INHIBITOR
  申请人：SYNPHAR LABORATORIES INC.

  公开号：EP0817795A1

  公开（公告）日：1998-01-14
• PROPHYLACTIC/THERAPEUTIC AGENT FOR CANCER
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP2379053A1

  公开（公告）日：2011-10-26
• US5986108A
  申请人：——

  公开号：US5986108A

  公开（公告）日：1999-11-16
• [EN] NOVEL 4-SUBSTITUTED-3-PEPTIDYL-AZETIDIN-2-ONE DERIVATIVES USEFUL AS CYSTEINE PROTEINASE INHIBITOR<br/>[FR] NOUVEAUX DERIVES 3-PEPTIDYL-AZETIDIN-2-ONE SUBSTITUEE EN 4 UTILES EN TANT QU'INHIBITEUR DES CYSTEINES PROTEINASES
  申请人：SYNPHAR LABORATORIES, INC.

  公开号：WO1996032408A1

  公开（公告）日：1996-10-17

  (EN) Certain 4-substituted-3-peptidyl-azetidin-2-one compounds exhibit excellent cysteine proteinase inhibitory activity which can be used in the treatment of different diseases such as muscular dystrophy, bone resorption, myocardial infarction and cancer metastasis. These compounds are 4-substituted-3-peptidyl-azetidin-2-ones of formula (I) or pharmaceutically acceptable salts thereof, wherein R1 is hydrogen; C1-C6 alkyl which is unsubstituted or substituted; R2 is selected from the group consisting of hydrogen; C1-C6 alkyl which is unsubstituted or substituted; -XR6 wherein X is O, S, SO, or SO2; R6 is C1-C6 alkyl which is unsubstituted or substituted. Peptidyl group is a 1-2 amino acid residue wherein the free NH2 is unsubstituted or substituted with a protective group selected from the group consisting of aryloxy carbonyl, alkoxy carbonyl, substituted alkanoyl, arylalkanoyl, arylalkenoyl, heterocyclealkanoyl, heterocyclealkenoyl alkylsulphonyl, arylsulphonyl, arylalkanylsulphonyl, arylalkensulphonyl, heterocyclealkanylsulphonyl, heterocyclealkensulphonyl, and heteroarylsulphonyl.(FR) Certains composés 3-peptidyl-azétidin-2-one substituée en 4 possèdent une excellente activité d'inhibition des cystéines protéinases, et on peut les utiliser dans le traitement de différentes maladies telles que la myopathie primitive progressive, la résorption osseuse, l'infarctus du myocarde et les métastases cancéreuses. Ces composés sont des 3-peptidyl-azétidin-2-ones substituées en 4 de la formule (I), ou des sels de celles-ci, acceptables sur le plan pharmacologique. Dans cette formule, R1 représente hydrogène, alkyle C1-C6 substitué ou non; R2 est choisi dans le groupe constitué par hydrogène, alkyle C1-C6 substitué ou non, -XR6 où X représente O, S, SO ou SO2 et R6 représente alkyle C1-C6 substitué ou non. Le groupe peptidyle est un reste d'acide aminé 1-2 dans lequel le groupe libre NH2 n'est pas substitué ou l'est par un groupe protecteur choisi dans le groupe constitué par aryloxy carbonyle, alcoxy carbonyle, alcanoyle substitué, arylalcanoyle, arylalcénoyle, hétérocycle-alcanoyle, hétérocyle-alcénoyle, alkylsulphonyle, arylsulphonyle, arylalcanylsulphonyle, arylalcènesulphonyle, hétérocycle-alcanylsulphonyle, hétérocycle-alcènesulphonyle et hétéroarylsulphonyle.