3-(acetylthio)-5-methylhexanoic acid | 169469-83-4

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: 3-(acetylthio)-5-methylhexanoic acid
• 英文别名: 3-Acetylsulfanyl-5-methylhexanoic acid
• CAS: 169469-83-4
• 化学式: C₉H₁₆O₃S
• 分子量: 204.29
• InChiKey: NCQBAXHLKYOPEJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  13
• 可旋转键数：
  6
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  79.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-(acetylthio)-5-methylhexanoic acid 在 sodium hydroxide 、 1-羟基苯并三唑 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 生成 N-(3-mercapto-5-methyl-1-oxohexyl)-L-phenylalanyl-L-tyrosine
  参考文献：
  名称：

  Exploration of neutral endopeptidase active site by a series of new thiol-containing inhibitors

  摘要：

  With the aim of characterizing the active site of the neutral endopeptidase [EC 3.4.24.11 (NEP)] and especially its putative S1 subsite, two series of new thiol inhibitors designed to interact with the S1, S'1, and S'2 subsites of the enzyme have been synthesized. These molecules correspond to the general formula HSCH(R1)CH(R2)CONHCH(R3)COOH (series I) and HSCH(R1)CH(R2)-CONHCH(R3)CONHCH(R4)COOH(series II). Due to the synthetic pathway used, these inhibitors were obtained as mixtures of four stereoisomers. HPLC separation of the stereoisomers of 17 HSCH[CH2CH(CH3)2]CH(CH2Ph)CONHCH(CH3)COOH allowed the stereochemical dependence of the inhibitory potency to be determined. The most active isomer 17b (IC50 = 3.6 nM) is assumed to have the S,S,S stereochemistry as deduced from both NMR and HPLC data. Although none of the inhibitors obtained were significantly more active than thiorphan, HSCH2CH(CH2Ph)-CONHCH2COOH (IC50 = 4 nM), which interacts only with the S'1 and S'2 subsites of NEP, their enhanced hydrophobicity is expected to improve their pharmacokinetic properties. An these compounds displayed low affinities for ACE (IC50s > 1 muM). The determination of the IC50s of two inhibitors of series II for NEP and for a mutated enzyme in which Arg102 was replaced by Glu102 allowed their mode of binding to the active site of NEP to be characterized. The R2 and R3 chains fit the S'1-S'2 subsites, while the R4 group is probably located outside the active site. Taken together these results indicate that the R1 chain of these inhibitors creates no additional stabilizing interactions with the active site of NEP. Two hypotheses may account for this: there is no hydrophobic S1 subsite in NEP or the inhibitors have structures which are too constrained for optimized interactions with the active site.

  DOI：

  10.1021/jm00053a011
• 作为产物：
  描述：

  (E)-5-甲基己-2-烯酸乙酯 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 生成 3-(acetylthio)-5-methylhexanoic acid
  参考文献：
  名称：

  Exploration of neutral endopeptidase active site by a series of new thiol-containing inhibitors

  摘要：

  With the aim of characterizing the active site of the neutral endopeptidase [EC 3.4.24.11 (NEP)] and especially its putative S1 subsite, two series of new thiol inhibitors designed to interact with the S1, S'1, and S'2 subsites of the enzyme have been synthesized. These molecules correspond to the general formula HSCH(R1)CH(R2)CONHCH(R3)COOH (series I) and HSCH(R1)CH(R2)-CONHCH(R3)CONHCH(R4)COOH(series II). Due to the synthetic pathway used, these inhibitors were obtained as mixtures of four stereoisomers. HPLC separation of the stereoisomers of 17 HSCH[CH2CH(CH3)2]CH(CH2Ph)CONHCH(CH3)COOH allowed the stereochemical dependence of the inhibitory potency to be determined. The most active isomer 17b (IC50 = 3.6 nM) is assumed to have the S,S,S stereochemistry as deduced from both NMR and HPLC data. Although none of the inhibitors obtained were significantly more active than thiorphan, HSCH2CH(CH2Ph)-CONHCH2COOH (IC50 = 4 nM), which interacts only with the S'1 and S'2 subsites of NEP, their enhanced hydrophobicity is expected to improve their pharmacokinetic properties. An these compounds displayed low affinities for ACE (IC50s > 1 muM). The determination of the IC50s of two inhibitors of series II for NEP and for a mutated enzyme in which Arg102 was replaced by Glu102 allowed their mode of binding to the active site of NEP to be characterized. The R2 and R3 chains fit the S'1-S'2 subsites, while the R4 group is probably located outside the active site. Taken together these results indicate that the R1 chain of these inhibitors creates no additional stabilizing interactions with the active site of NEP. Two hypotheses may account for this: there is no hydrophobic S1 subsite in NEP or the inhibitors have structures which are too constrained for optimized interactions with the active site.

  DOI：

  10.1021/jm00053a011

文献信息

• Exploration of neutral endopeptidase active site by a series of new thiol-containing inhibitors
  作者：Isabel Gomez-Monterrey、Serge Turcaud、Evelyne Lucas、Luce Bruetschy、Bernard P. Roques、Marie Claude Fournie-Zaluski

  DOI：10.1021/jm00053a011

  日期：1993.1

  With the aim of characterizing the active site of the neutral endopeptidase [EC 3.4.24.11 (NEP)] and especially its putative S1 subsite, two series of new thiol inhibitors designed to interact with the S1, S'1, and S'2 subsites of the enzyme have been synthesized. These molecules correspond to the general formula HSCH(R1)CH(R2)CONHCH(R3)COOH (series I) and HSCH(R1)CH(R2)-CONHCH(R3)CONHCH(R4)COOH(series II). Due to the synthetic pathway used, these inhibitors were obtained as mixtures of four stereoisomers. HPLC separation of the stereoisomers of 17 HSCH[CH2CH(CH3)2]CH(CH2Ph)CONHCH(CH3)COOH allowed the stereochemical dependence of the inhibitory potency to be determined. The most active isomer 17b (IC50 = 3.6 nM) is assumed to have the S,S,S stereochemistry as deduced from both NMR and HPLC data. Although none of the inhibitors obtained were significantly more active than thiorphan, HSCH2CH(CH2Ph)-CONHCH2COOH (IC50 = 4 nM), which interacts only with the S'1 and S'2 subsites of NEP, their enhanced hydrophobicity is expected to improve their pharmacokinetic properties. An these compounds displayed low affinities for ACE (IC50s > 1 muM). The determination of the IC50s of two inhibitors of series II for NEP and for a mutated enzyme in which Arg102 was replaced by Glu102 allowed their mode of binding to the active site of NEP to be characterized. The R2 and R3 chains fit the S'1-S'2 subsites, while the R4 group is probably located outside the active site. Taken together these results indicate that the R1 chain of these inhibitors creates no additional stabilizing interactions with the active site of NEP. Two hypotheses may account for this: there is no hydrophobic S1 subsite in NEP or the inhibitors have structures which are too constrained for optimized interactions with the active site.