(1S)-N_b-α-phenylethyl indole-3-glyoxylamide | 174906-24-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (1S)-N_b-α-phenylethyl indole-3-glyoxylamide
• 英文别名: 2-(1H-indol-3-yl)-2-oxo-N-[(1S)-1-phenylethyl]acetamide
• CAS: 174906-24-2
• 化学式: C₁₈H₁₆N₂O₂
• mdl: MFCD04472748
• 分子量: 292.337
• InChiKey: JCQKMELKMGOGMR-LBPRGKRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  62
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (1S)-N_b-α-phenylethyl indole-3-glyoxylamide 在 lithium aluminium tetrahydride 、 三氯化铝 作用下， 以 四氢呋喃 为溶剂， 以62%的产率得到(S)-N-(2-(1H-indol-3-yl)ethyl)-1-phenylethanamine
  参考文献：
  名称：

  Asymmetric Pictet-Spengler Reaction Using a-Methylbenzylamine as a Chiral Auxiliary Group

  摘要：

  DOI：

  10.3987/com-95-s44
• 作为产物：
  描述：

  吲哚-3-乙醛酰氯 、 (S)-(-)- α-甲基苄胺 在 三乙胺 作用下， 以 甲苯 为溶剂， 以51%的产率得到(1S)-N_b-α-phenylethyl indole-3-glyoxylamide
  参考文献：
  名称：

  Novel N-(Arylalkyl)indol-3-ylglyoxylylamides Targeted as Ligands of the Benzodiazepine Receptor:  Synthesis, Biological Evaluation, and Molecular Modeling Analysis of the Structure−Activity Relationships

  摘要：

  A series of N-(arylalkyl)indol-3-ylglyoxylylamides (4-8) was synthesized as ligands of the benzodiazepine receptor (BzR) and tested for their ability to displace [H-3]flumazenil from bovine brain membranes. The new compounds, bearing a branched (4) or a geometrically constrained benzyl/phenylethyl amide side chain (5-8), represent the continuation of our research on N-benzylindol-3-ylglyoxylylamides 1 (Da Settimo et al., 1996), N ' -phenylindol-3-ylglyoxylohydrazides 2 (Da Settimo et al., 1998), and N-(indol-3-ylglyoxylyl)alanine derivatives 3 (Primofiore et al., 1989). A few indoles belonging to the previously investigated benzylamides 1 and phenylhydrazides 2 were synthesized and tested to enrich the SARs in these two series. The affinities and the GABA ratios of selected compounds for clonal mammalian alpha (1)beta (2)gamma (2), alpha (3)beta (2)gamma (2), and alpha (5)beta (3 gamma2) BzR subtypes were also determined. It was hypothesized that the reduced flexibility of indoles 4-8 would both facilitate the mapping of the BzR binding cleft and increase the chances of conferring selectivity for the considered receptor subtypes. In the series of indoles 4, the introduction of a methyl group on the benzylic carbon with the R configuration improved affinity of the 5-substituted (5-Cl and 5-NO2) derivatives, whereas it was detrimental for their 5-unsubtituted (5-H) counterparts. All S enantiomers were less potent than the R ones. Replacement of the methyl with hydrophilic substituents on the benzylic carbon lowered affinity. The isoindolinylamide side chain was tolerated if the 5-position was unsubstituted (K-i of 5a 123 nM), otherwise affinity was abolished (5b, c). All the 2-indanylamides 6 and (S)-1-indanylamides 8 were devoid of any appreciable affinity. The 5-Cl and 5-NO2 (R)-1-indanylamides 7b (K-i 80 nM) and 7c (K-i 28 nM) were the most potent among the indoles 5-8 geometrically constrained about the side chain. The 5-H (R)-1-indanylamide 7a displayed a lower affinity (K-i 675 nM). The SARs developed from the new compounds, together with those collected from our previous studies, confirmed the hypothesis of different binding modes for 5-substituted and 5-unsubstituted indoles, suggesting that the shape of the lipophilic pocket L-1 (notation in accordance with Cook's BzR topological model) is asymmetric and highlighted the stereoelectronic and conformational properties of the amide side chain required for high potency. Several of the new indoles showed selectivity for the alpha (1)beta (2)gamma (2) subtype compared with the alpha (3)beta (2)gamma (2) and alpha (5)beta (3)gamma (2) subtypes (e.g.: 4t and 7c bind to these three BzR isoforms with Ki values of 14 nM, 283 nM, 239 nM, and 9 nM, 1960 nM, 95 nM, respectively). The GABA ratios close to unity exhibited by all the tested compounds on each BzR subtype were predictive of an efficacy profile typical of antagonists.

  DOI：

  10.1021/jm010827j