2-氟-2-丙基戊-4-烯酸 | 164228-14-2

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 中文名称: 2-氟-2-丙基戊-4-烯酸
• 英文名称: Alpha-fluoro-4-ene-Valproic acid
• 英文别名: 2-fluoro-2-propylpent-4-enoic acid
• CAS: 164228-14-2
• 化学式: C₈H₁₃FO₂
• 分子量: 160.188
• InChiKey: CYSFMOXXKZIWLO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  11
• 可旋转键数：
  5
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  37.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  2-氟-2-丙基戊-4-烯酸乙酯 以80%的产率得到2-氟-2-丙基戊-4-烯酸
  参考文献：
  名称：

  Fluorinated Analogs as Mechanistic Probes in Valproic Acid Hepatotoxicity: Hepatic Microvesicular Steatosis and Glutathione Status

  摘要：

  It is postulated that the hepatotoxicity of valproic acid (VPA) results from the mitochondrial beta-oxidation of its cytochrome P450 metabolite, 2-propyl-4-pentenoic acid (4-ene VPA), to 2-propyl-(E)-2,4-pentadienoic acid ((E)-2,4-diene VPA) which, in the CoA thioester form, either depletes GSH or produces a putative inhibitor of beta-oxidation enzymes. In order to test this hypothesis, 2-fluoro-2-propyl-4-pentenoic acid (alpha-fluoro-4-ene VPA) which was expected to be inert to beta-oxidative metabolism was synthesized and its effect on rat liver studied in comparison with that of 4-ene VPA. Similarly, the known hepatotoxicant 4-pentenoic acid (4-PA) and 2,2-difluoro-4-pentenoic acid (F-2-4-PA) were compared. Male Sprague-Dawley rats (150-180 g, 4 rats per group) were dosed ip with 4-ene VPA (0.7 mmol/kg per day), 4-PA (1.0 mmol/kg per day), or equivalent amounts of their alpha-fluorinated analogues for 5 days. Both 4-ene VPA and 4-PA induced severe hepatic microvesicular steatosis (> 85% affected hepatocytes), and 4-ene VPA produced mitochondrial alterations. By contrast, alpha-fluoro-4-ene VPA and F-2-4-PA were not observed to cause morphological changes in the liver. The major metabolite of 4-ene VPA in the rat urine and serum was the beta-oxidation product (E)-2,4-diene VPA. The N-acetylcysteine (NAC) conjugate of (E)-2,4-diene VPA was also found in the urine. Neither (E)-2,4-diene VPA nor the NAC conjugate could be detected in the rats administered alpha-fluoro-4-ene VPA. In a second set of rats (3 rats per group), total liver GSH levels were determined to be depleted to 56% and 72% of control following doses of 4-ene VPA (1.4 mmol/kg); and equivalent alpha-fluoro-4-ene VPA, respectively. Mitochondrial GSH remained unchanged in the (alpha-fluoro-4-ene VPA treated group but was reduced to 68% of control in the rats administered 4-ene VPA. These results strongly support the theory that hepatotoxicity of 4-ene VPA, and possibly VPA itself, is mediated largely through beta-oxidation of 4-ene VPA to reactive intermediates that are capable of depleting mitochondrial GSH.

  DOI：

  10.1021/tx00047a006

文献信息

• ALPHA-FLUORO ALKYNOIC ACIDS WITH ANTICONVULSANT ACTIVITY
  申请人：AMERICAN BIOGENETIC SCIENCES, INC.

  公开号：EP1089960A1

  公开（公告）日：2001-04-11
• 2-FLUORO-2-ALKYL ALKANOAMIDES WITH ANTICONVULSANT ACTIVITY
  申请人：AMERICAN BIOGENETIC SCIENCES, INC.

  公开号：EP1089962A1

  公开（公告）日：2001-04-11
• US6184401B1
  申请人：——

  公开号：US6184401B1

  公开（公告）日：2001-02-06
• [EN] 2-FLUORO-2-ALKYL ALKANOAMIDES WITH ANTICONVULSANT ACTIVITY<br/>[FR] 2-FLUORO-2-ALKYL ALKANOAMIDES AVEC ACTIVITE ANTIEPILEPTIQUE
  申请人：AMERICAN BIOGENETIC SCIENCES INC.

  公开号：WO1999067199A1

  公开（公告）日：1999-12-29

  (EN) Alpha-fluorinated alkanoamides of formula (I), and pharmaceutical compositions containing them, are provided. The compounds and compositions are useful for the treatment and prevention of seizures such as are associated with epilepsy. The compounds of the invention exhibit an improved therapeutic ratio, relative to valproic acid, with regard to sedation and teratogenic potential, and exhibit improved pharmacokinetics and pharmacodynamics.(FR) L'invention concerne des 2-fluoro-2-alkyl alkanoamides représentés par la formule I, et les compositions pharmaceutiques les contenant. Ces composés et ces compositions sont utiles pour traiter et prévenir des crises telles que celles associées à l'épilepsie. Les composés de l'invention présentent un rapport thérapeutique amélioré par rapport à l'acide valproïque, en ce qui concerne les effets sédatifs et le potentiel tératogène. Ils présentent également une phamacocinétique et une pharmacodynamie améliorées.
• [EN] ALPHA-FLUORO ALKYNOIC ACIDS WITH ANTICONVULSANT ACTIVITY<br/>[FR] ACIDES ALCYNIQUES ALPHA-FLUORES A ACTION ANTICONVULSIVANTE
  申请人：AMERICAN BIOGENETIC SCIENCES INC.

  公开号：WO1999067195A1

  公开（公告）日：1999-12-29

  (EN) Alpha-fluorinated alkynoic acids of structure (I) wherein R1 is C3 to C10 alkyl, C3 to C6 cycloalkyl, or cyclopropylmethyl, and R2 is C1 to C3 alkyl or cyclopropyl, and the pharmaceutically acceptable salts, esters, and amides thereof; and pharmaceutical compositions containing these compounds are provided, which are useful for the treatment and prevention of seizures such as are associated with epilepsy. The compounds of the invention exhibit reduced side effects, relative to valproic acid, with regard to sedation and teratogenic potential.(FR) L'invention concerne des acides alcyniques alfa-fluorés ayant la structure: (I) dans laquelle R1 est un alkyle C3-C10, un cycloalkyle ou cyclopropylméthyle C3-C6, et R2 est un alkyle ou cyclopropyle C1-C3, ainsi que leurs sels pharmaceutiquement acceptables et leurs esters et amides, de même que les compositions pharmaceutiques qui contiennent ces composés. Ils sont utiles pour traiter et prévenir les crises d'épilepsie et similaires. Les composés de l'invention manifestent des effets secondaires réduits par rapport à l'acide valproïque en ce qui concerne le potentiel sédatif et tératogène.