(8-isobutyl-6-phenyl-1,2,4-triazolo<4,3-a>pyrazin-3-yl)acetic acid | 128901-32-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: (8-isobutyl-6-phenyl-1,2,4-triazolo<4,3-a>pyrazin-3-yl)acetic acid
• 英文别名: 8-isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-ylacetic acid；(8-isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-yl)acetic acid；2-[8-(2-Methylpropyl)-6-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]acetic acid
• CAS: 128901-32-6
• 化学式: C₁₇H₁₈N₄O₂
• 分子量: 310.356
• InChiKey: FZPTXRRKEANMSJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  80.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropyl hexanoic acid n-butyl amide 、 (8-isobutyl-6-phenyl-1,2,4-triazolo<4,3-a>pyrazin-3-yl)acetic acid 在 1-羟基苯并三唑一水物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 生成
  参考文献：
  名称：

  1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 2. Synthesis, biological properties and molecular modeling of hydroxyethylene isostere derivatives

  摘要：

  A series of inhibitors of human renin have been synthesized, derived from combination of a 2-(8-propyl-6-pyridin-3-yl-1,2,4-triazolo[4,3-a]pyrazin-3-yl)- 3-pyridin- 3-ylpropionic acid moiety 6c with the hydroxyethylene isostere of the scissile amide bond (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid (ChaOH--Val). The more potent members of this series showed good inhibitory activity against partially purified human renin, 7d, for example, having an IC50 of 0.2 nM. Structure-activity relationships for these compounds were consistent with their binding to the S4-S2' sites of human renin. Analogues 7e and 7h-k with a variety of substituents at the C-terminus all had in vitro IC50S less than 1 nM. In contrast with the majority of previously reported inhibitors of similar potency, these compounds contain no natural amino acid fragments. When administered intravenously to anesthetized, sodium-depleted marmosets at doses of 0.3-3.0 mg/kg, compound 7d caused a marked reduction in mean arterial pressure. Following oral administration at 30 mg/kg in the same animal model, 7d again elicited a significant fall in mean arterial pressure, accompanied by suppression of plasma renin activity lasting up to 3 h after dosing.

  DOI：

  10.1021/jm00171a006
• 作为产物：
  描述：

  sodium 4-methyl-2-oxovalerate 在 乙酸铵 、 sodium hydroxide 、 对甲苯磺酸 、 一水合肼 、 1-羟基苯并三唑一水物 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 二甲基亚砜 、 乙酸乙酯 、 甲苯 为溶剂， 反应 14.0h， 生成 (8-isobutyl-6-phenyl-1,2,4-triazolo<4,3-a>pyrazin-3-yl)acetic acid
  参考文献：
  名称：

  1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 1. Synthesis and biological properties of alkyl alcohol and statine derivatives

  摘要：

  A series of 1,2,4-triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity, which incorporate (1S,2S)-2-amino-1,3-dicyclohexyl-1-hydroxypropane, statine (Sta), and (3S,4S)-4-amino-5-cyclohexyl-3-hydroxy-pentanoic acid (ACHPA) transition-state mimetics, have been prepared. Structure-activity relationships for renin inhibitory activity in the series are consistent with the 2-[8-isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-yl]-3-(3 pyridyl)propionic acid moiety 10b acting as a non-peptidic replacement for the P4-P2 (Pro-Phe-His) residues of the natural substrate angiotensinogen. Compounds 12m, 12o and 12q were potent inhibitors of partially purified human renin (IC50 values 1.7, 6.8, and 3.7 nM, respectively), and also effectively lowered blood pressure in anesthetized, sodium depleted marmosets following intravenous administration. On oral administration however, no blood pressure lowering activity could be detected, and absorption studies in bile duct cannulated rats indicate that this may be due primarily to poor oral absorption, rather than rapid biliary excretion. The reason for the observed poor oral activity is not clear, but it seems unlikely that poor aqueous solubility or metabolic instability to gut enzymes are rate-determining, and other factors such as high molecular weight may also be very important.

  DOI：

  10.1021/jm00171a005

文献信息

• Heterocyclische Verbindungen mit reninhemmenden Eigenschaften, Verfahren zu ihrer Herstellung und ihre Verwendung
  申请人：HOECHST AKTIENGESELLSCHAFT

  公开号：EP0519434A2

  公开（公告）日：1992-12-23

  Heterocyclische Verbindungen der Formel (I), in welcher die Reste folgende Bedeutungen haben: R1 z.B. Propyl und Isobutyl R2 z.B. Phenyl oder Pyridyl R3 z.B. Wasserstoff, R4 z.B. Cyclohexylmethyl R5 z.B Wasserstoff oder Hydroxy R6 ein Rest der Formel (II), wobei R7 z.B Wasserstoff, Z für einen 5- bis 7-gliedrigen heterocyclischen Ring und s 0, 1, 2, 3 oder 4 bedeutet; sind potente Renin-hemmende Verbindungen.

  式 (I) 的杂环化合物、 其中基团的含义如下： R1 如丙基和异丁基 R2 如苯基或吡啶基 R3 如氢 R4 如环己基甲基 R5 如氢或羟基 R6 是式(II)的基团、 其中 R7 是氢等、 Z 是 5 至 7 元杂环，且 s 为 0、1、2、3 或 4； 是强效的肾素抑制化合物。
• ROBERTS, DAVID A.;BRADBURY, ROBERT H.;BROWN, DAVID;FAULL, ALAN;GRIFFITHS,+, J. MED. CHEM., 33,(1990) N, C. 2326-2334
  作者：ROBERTS, DAVID A.、BRADBURY, ROBERT H.、BROWN, DAVID、FAULL, ALAN、GRIFFITHS,+

  DOI：——

  日期：——
• BRADBURY, ROBERT H.;MAJOR, JOHN S.;OLDHAM, ALEC A.;RIVETT, JANET E.;ROBER+, J. MED. CHEM., 33,(1990) N, C. 2335-2342
  作者：BRADBURY, ROBERT H.、MAJOR, JOHN S.、OLDHAM, ALEC A.、RIVETT, JANET E.、ROBER+

  DOI：——

  日期：——
• US5091425A
  申请人：——

  公开号：US5091425A

  公开（公告）日：1992-02-25
• 1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 2. Synthesis, biological properties and molecular modeling of hydroxyethylene isostere derivatives
  作者：Robert H. Bradbury、John S. Major、Alec A. Oldham、Janet E. Rivett、David A. Roberts、Anthony M. Slater、David Timms、David Waterson

  DOI：10.1021/jm00171a006

  日期：1990.9

  A series of inhibitors of human renin have been synthesized, derived from combination of a 2-(8-propyl-6-pyridin-3-yl-1,2,4-triazolo[4,3-a]pyrazin-3-yl)- 3-pyridin- 3-ylpropionic acid moiety 6c with the hydroxyethylene isostere of the scissile amide bond (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid (ChaOH--Val). The more potent members of this series showed good inhibitory activity against partially purified human renin, 7d, for example, having an IC50 of 0.2 nM. Structure-activity relationships for these compounds were consistent with their binding to the S4-S2' sites of human renin. Analogues 7e and 7h-k with a variety of substituents at the C-terminus all had in vitro IC50S less than 1 nM. In contrast with the majority of previously reported inhibitors of similar potency, these compounds contain no natural amino acid fragments. When administered intravenously to anesthetized, sodium-depleted marmosets at doses of 0.3-3.0 mg/kg, compound 7d caused a marked reduction in mean arterial pressure. Following oral administration at 30 mg/kg in the same animal model, 7d again elicited a significant fall in mean arterial pressure, accompanied by suppression of plasma renin activity lasting up to 3 h after dosing.