The 2011 E. B. Hershberg Award for Important Discoveries in Medicinally Active Substances: (1S,3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic Acid (CPP-115), a GABA Aminotransferase Inactivator and New Treatment for Drug Addiction and Infantile Spasms
The 2011 E. B. Hershberg Award for Important Discoveries in Medicinally Active Substances: (1S,3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic Acid (CPP-115), a GABA Aminotransferase Inactivator and New Treatment for Drug Addiction and Infantile Spasms
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DOI：
10.1021/jm201650r
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发表时间：
2012-01-26
影响因子：
7.3
通讯作者：
Silverman, Richard B.
中科院分区：
文献类型：
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作者：
Silverman, Richard B.
酶是药物设计的极佳靶标，因为许多疾病，或者至少是疾病的症状，可能是由于一个特定分子的缺乏、一个分子的过量、外来生物的感染或细胞的异常生长而引起的；所有这些病因都可以通过特定的酶抑制来调节。酶的抑制阻止底物转化为产物，从而增加底物的浓度和降低产物的浓度，从而使这些特定分子的不足或过剩分别正常化。通过靶向一种对外来有机体或肿瘤细胞的生命至关重要的酶，就有可能摧毁该有机体或细胞，或者至少阻止其复制。这一奖项讲座的视角利用了一种方法来增加单一分子的浓度，即γ-氨基丁酸，用于治疗癫痫障碍和药物成瘾。参与调节脑神经元活动的两种主要神经递质是分布最广泛的抑制性神经递质之一的γ-氨基丁酸和兴奋性神经递质L-谷氨酸。1γ-氨基丁酸的浓度受两种依赖于吡哆醛5‘-磷酸的酶调节，即L-谷氨酸脱羧酶和γ-氨基丁酸转氨酶，前者催化L-谷氨酸转化为γ-氨基丁酸，后者将γ-氨基丁酸降解为琥珀半醛，α-酮戊二酸转化为L-谷氨酸(图1)。2脑内GABA浓度降至阈值以下时，出现惊厥；3提高脑内GABA水平可终止癫痫发作，是治疗癫痫的有效途径。4不幸的是，服用GABA药丸来提高大脑GABA水平是徒劳的，因为GABA通过血−脑屏障的运输非常差5，很容易从大脑排出。6癫痫可由多种原因引起；因此，癫痫不是一种单一的疾病，癫痫活动的发生率在世界上非常普遍。事实上，当癫痫被广义地定义为任何以反复惊厥发作为特征的疾病时，那么1−2%的世界人口可以被归类为癫痫。因此，几个世纪以来，人们一直在寻找抗惊厥药物。直到近60年前，苯海因(Dilantin)被引入药品市场，任何一种特定的抗惊厥药物才被广泛使用。然而，这种药物不是普遍适用的。事实上，全世界超过四分之一的癫痫患者(约1200万人)对任何市场上销售的抗癫痫药物都没有反应。因此，对新的抗惊厥药物的需求是巨大的。癫痫的一个原因是大脑中γ-氨基丁酸/L-谷氨酸水平的失衡。GABA和/或产生GABA的酶GAD浓度的降低不仅与癫痫相关的症状11有关，还与其他几种神经系统疾病有关，如亨廷顿舞蹈症、12、13帕金森病、14、15阿尔茨海默病、16和迟发性运动障碍。17已经采取了几种方法来增加大脑中GABA的浓度。一种方法是制造GABA，18，19的前药，但除了普罗贝利外，这一方法并不是非常成功。另一种提高大脑−水平的方法是使用一种化合物，这种化合物可以穿过血中的GABA脑屏障，然后抑制或灭活GABA-AT，这是一种降解GABA的酶。假设对GAD的抑制很小，这种酶的抑制会导致GABA的积聚。这在没有…的情况下有效地抑制了过度的神经活动
Enzymes are excellent targets for drug design because many diseases, or at least the symptoms of disease, can arise from a deficiency of one specific molecule, an excess of one molecule, infestation of a foreign organism, or aberrant cell growth; all of these etiologies can be modulated by specific enzyme inhibition. Inhibition of an enzyme prevents the conversion of substrate to product, thereby increasing the concentration of the substrate and decreasing the concentration of the product, thereby normalizing a deficiency or excess, respectively, of those particular molecules. By targeting an enzyme essential for the life of a foreign organism or tumor cell, it is possible to destroy that organism or cell or, at least, prevent it from replicating. This Award Lecture Perspective takes advantage of an approach to increase the concentration of a single molecule, namely, γ-aminobutyric acid (GABA), for the treatment of seizure disorders and drug addiction. The two principal neurotransmitters involved in the regulation of brain neuronal activity are GABA, one of the most widely distributed inhibitory neurotransmitters, and L-glutamic acid, an excitatory neurotransmitter. 1 The concentration of GABA is regulated by two pyridoxal 5′-phosphate (PLP) dependent enzymes, L-glutamic acid decarboxylase (GAD), which catalyzes the conversion of L-glutamate to GABA, and GABA aminotransferase (GABA-AT), which degrades GABA to succinic semialdehyde (SSA) and converts α-ketoglutarate to L-glutamic acid (Figure 1). 2 When the concentration of GABA diminishes below a threshold level in the brain, convulsions result; 3 raising the brain GABA levels terminates the seizure and is an effective approach for the treatment of epilepsy. 4 Unfortunately, it is futile to take GABA pills to raise the brain GABA levels because GABA is transported across the blood− brain barrier very poorly 5 and is effluxed from the brain readily. 6 Seizures can arise from numerous etiologies; therefore, epilepsy is not a single disease, and the incidence of seizure activity is very prevalent in the world. In fact, when epilepsy is defined broadly as any disease characterized by recurring convulsive seizures, then 1− 2% of the world population can be classified as having epilepsy. 7 Consequently, anticonvulsant agents have been sought for centuries. Not until diphenylhydantoin (Dilantin) was introduced onto the drug market almost 60 years ago was any particular anticonvulsant drug widely used. 8 However, this drug is not generally applicable. In fact, more than one-quarter of epileptic patients worldwide (about 12 million people) do not respond to any marketed anticonvulsant drug. 5 Therefore, the need for new anticonvulsant drugs is great. 9One cause for epilepsy is an imbalance in the GABA/L-glutamate brain levels. A reduction in the concentrations of GABA and/or of the enzyme GAD, 10 which produces GABA, has been implicated not only in the symptoms associated with epilepsy 11 but also with several other neurological diseases such as Huntington’s chorea, 12, 13 Parkinson’s disease, 14, 15 Alzheimer’s disease, 16 and tardive dyskinesia. 17 Several approaches have been taken to increase the brain concentrations of GABA. One approach has been to make prodrugs of GABA, 18, 19 but except for progabide, this has not been highly successful. Another approach taken to increase brain GABA levels is the use of a compound that crosses the blood− brain barrier and then inhibits or inactivates GABA-AT, the enzyme that degrades GABA. Inhibition of this enzyme causes a buildup of GABA, assuming that inhibition of GAD is minimal. This effectively dampens excessive neural activity without …