Pharmacokinetic analysis and antiepileptic activity of tetramethylcyclopropane analogues of valpromide
Pharmacokinetic analysis and antiepileptic activity of tetramethylcyclopropane analogues of valpromide
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DOI：
10.1023/a:1016055517724
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发表时间：
1996-02-01
影响因子：
3.7
通讯作者：
Yagen, B
中科院分区：
文献类型：
--
作者：
Bialer, M;Hadad, S;Yagen, B
目的.本研究通过对丙戊酰胺四甲基环丙烷类似物（VPD）和丙戊酸四甲基环丙烷甲酰胺衍生物（VPA）的结构、药动学和药效学关系（SPPR）的研究，探讨了其作为新型抗癫痫药物的应用前景以下三种VPD环丙烷类似物的抗惊厥活性和神经毒性：2，2，3，3-四甲基环丙烷甲酰胺（TMCD）、N-甲基TMCD（M-TMCD）和N-[（2，2，3，3-四甲基环丙基）羰基]-甘氨酰胺（TMC-GLD）。这三种化合物在小鼠和大鼠中表现出良好的抗惊厥作用，因为它们是代谢稳定的VPD类似物它们没有被生物转化为其非活性酸2，2，3，3-四甲基环丙烷羧酸（TMCA）。M-TMCD代谢为TMCD，TMC-GLD部分生物转化为其甘氨酸类似物N-[（2，2，3，3-四甲基环丙基）羰基]-甘氨酸（TMC-GLN）。与TMC-GLN不同，上述酰胺类化合物具有较低的清除率和相对较长的半衰期。结论，与VPD生物转化为VPA相反，上述环丙烷衍生物对酰胺-酸生物转化稳定。TMCD和M-TMCD表明，VPD的环状类似物，如其脂肪族异构体，必须在羰基的β位上具有两个取代基，如在TMCD的情况下，或在α位和β位上具有取代基，如在VPD异构体缬沙坦（VCD）中。本文讨论了VPD的四甲基环丙烷类似物的抗癫痫潜力，其在动物模型中比VPA更有效，并且可能是非致畸性和非肝毒性的。
Purpose. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the utilization of tetramethylcyclopropane analogues of valpromide (VPD), or tetramethylcyclopropane carboxamide derivatives of valproic acid (VPA) as new antiepileptics.Methods, The study was carried out by investigating the pharmacokinetics in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following three cyclopropane analogues of VPD: 2,2,3,3-tetramethylcyclopropane carboxamide (TMCD), N-methyl TMCD (M-TMCD) and N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycinamide (TMC-GLD).Results, The three investigated compounds showed a good anticonvulsant profile in mice and rats due to the fact that they were metabolically stable VPD analogues which were not biotransformed to their nonactive acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid (TMCA). M-TMCD was metabolized to TMCD and TMC-GLD underwent partial biotransformation to its glycine analogue N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycine (TMC-GLN). Unlike TMC-GLN, the above mentioned amides had low clearance and a relatively long half life.Conclusions, In contrast to VPD which is biotransformed to VPA, the aforementioned cyclopropane derivatives were found to be stable to amide-acid biotransformation. TMCD and M-TMCD show that cyclic analogues of VPD, like its aliphatic isomers, must have either two substitutions at the beta position to the carbonyl, such as in the case of TMCD, or a substitution in the alpha and in the beta positions like in the VPD isomer, valnoctamide (VCD). This paper discusses the antiepileptic potential of tetramethylcyclopropane analogues of VPD which are in animal models more potent than VPA and may be non-teratogenic and non-hepatotoxic.