methyl (2S)-2-(N-benzyloxycarbonyl)amino-5-[(hydroxy)phosphinyl]pentanoate | 1218782-00-3

• 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: methyl (2S)-2-(N-benzyloxycarbonyl)amino-5-[(hydroxy)phosphinyl]pentanoate
• 英文别名: [(4S)-4-(N-benzyloxycarbonyl)amino-4-methoxycarbonylbutyl]phosphinic acid
• CAS: 1218782-00-3
• 化学式: C₁₄H₂₀NO₆P
• 分子量: 329.29
• InChiKey: MKADXTYXIPPCGU-LBPRGKRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  22.0
• 可旋转键数：
  8.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  101.93
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  五氟苯甲醛 、 methyl (2S)-2-(N-benzyloxycarbonyl)amino-5-[(hydroxy)phosphinyl]pentanoate 在 N,O-双三甲硅基乙酰胺 作用下， 以 二氯甲烷 为溶剂， 生成 [(3S)-3-(N-benzyloxycarbonyl)amino-3-methoxycarbonylpropyl][(2,3,4,5,6-pentafluorophenyl)hydroxymethyl]phosphinic acid
  参考文献：
  名称：

  Increased Potency and Selectivity for Group III Metabotropic Glutamate Receptor Agonists Binding at Dual sites

  摘要：

  A group III metabotropic glutamate (mGlu) receptor agonist (PCEP) was identified by virtual HTS. This orthosteric ligand is composed by an L-AP4-derived fragment that mimics glutamate and a chain that binds into a neighboring pocket, offering possibilities to improve affinity and selectivity. Herein we describe a series of derivatives where the distal chain is replaced by an aromatic or heteroaromatic group. Potent agonists were identified, including some with a mGlu(4) subtype preference, e.g., 17m (LSP1-2111) and 16g (LSP4-2022). Molecular modeling suggests that aromatic functional groups may bind at either one of the two chloride regulatory sites. These agonists may thus be considered as particular bitopic/dualsteric ligands. 17m was shown to reduce GABAergic synaptic transmission at striatopallidal synapses. We now demonstrate its inhibitory effect at glutamatergic parallel fiber-Purkinje cell synapses in the cerebellar cortex. Although these ligands have physicochemical properties that are markedly different from typical CNS drugs, they hold significant therapeutic potential.

  DOI：

  10.1021/acs.jmedchem.7b01438
• 作为产物：
  描述：

  methyl (2S)-2-benzyloxycarboxamido-4-pentenoate 在 偶氮二异丁腈 、 次磷酸 作用下， 以 甲醇 、 水 为溶剂， 反应 5.0h， 以52%的产率得到methyl (2S)-2-(N-benzyloxycarbonyl)amino-5-[(hydroxy)phosphinyl]pentanoate
  参考文献：
  名称：

  A Virtual Screening Hit Reveals New Possibilities for Developing Group III Metabotropic Glutamate Receptor Agonists

  摘要：

  (R)-PCEP (3-amino-3-carboxypropy1-2'-carboxyethyl phosphinic acid, 1), a new metabotropic glutamate receptor 4 (mGlu4R) agonist, was discovered in a previously reported virtual screening. The (S)-enantiomer and a series of derivatives were synthesized and tested on recombinant mGlu4 receptors. A large number of derivatives activated this receptor but was not able to discriminate between mGlu4 and mGlu8 receptors. The most potent ones 6 and 12 displayed an EC50 of 1.0 +/- 0.2 mu M at mGlu4R. Interestingly these agonists with longer alkyl chains revealed a new binding pocket adjacent to the glutamate binding site, which is lined with residues that differ among the mGluR subtypes and that will allow the design of more selective compounds. Additionally 6 was able to activate mGlu7 receptor with an EC50 of 43 +/- 16 mu M and is thus significantly more potent than L-AP4 (EC50 of 249 +/- 106 mu M).

  DOI：

  10.1021/jm901523t