Prodrugs of NAAG Peptidase Inhibitors for the Treatment of Schizophrenia

描述（由申请人提供）：精神分裂症是一种慢性、严重、致残的脑部疾病。将近1%的人会在一生中患上精神分裂症——每年有超过200万美国人患有这种疾病。精神分裂症世界市场在2004年创造了近120亿美元的总收入，并仍在稳步增长。非典型抗精神病药物，如氯氮平、利培酮和奥氮平被广泛用于治疗精神分裂症，但在缓解不同患者出现的阳性、阴性和认知症状方面并不完全有效。这些药物主要通过拮抗多巴胺和血清素受体起作用。然而，大量文献支持谷氨酸能回路在精神分裂症人类和动物模型中介导精神分裂症症状的参与。因此，谷氨酸受体配体作为治疗这种疾病的潜在替代和辅助疗法正在积极分析中。其中包括NMDA受体上甘氨酸位点的激活剂和II组代谢谷氨酸受体（mGluR）激动剂。n -乙酰氨基谷氨酸（NAAG）是哺乳动物神经系统中第三常见的递质，也是II类mGluR （mGluR3>>mGluR2）选择性激动剂。在n -乙酰天冬氨酸（NAA）和谷氨酸（Glu）被释放到突触空间后，它被细胞外肽酶（GCPII和III）灭活。抑制GCPII和III增加NAAG水平，从而激活突触前II组mGluRs。II组mGluR激活抑制谷氨酸的释放并减轻苯环利定（PCP）引起的精神分裂症样行为症状。我们的研究小组证明NAAG肽酶抑制和随后NAAG激活II组mGluR也减少了这些行为，因此可能代表了一种治疗精神分裂症和急性PCP中毒的新方法。经过广泛的SAR研究，我们的研究小组已经确定了一些基于尿素的化合物，包括zj43， zj11和zj17，作为NAAG肽酶抑制剂具有纳米摩尔效价。在精神分裂症大鼠模型中，全身给药NAAG肽酶抑制剂ZJ 43可减少pcp诱导的行为，而ZJ 43的这种作用可被II组mGluR拮抗剂LY341495阻断。然而，存在一个重要的问题，即这些化合物过于极性，不易穿透血脑屏障（BBB），无法推进人体临床研究。前体药物的发展将提供精确的剂量输送到大脑的手段，以提高其疗效，并使用较低的剂量范围，以避免不必要的全身副作用的问题。本研究项目的长期目标是开发这些NAAG肽酶抑制剂作为精神分裂症的新疗法或辅助疗法。为了加快这些化合物在人体临床试验中的开发和应用，本研究计划的直接目标是开发新的前药，以提高候选NAAG肽酶抑制剂的血脑屏障穿透能力，从而提高其疗效。值得注意的是，我们最近的初步数据表明，在我们的pcp诱导的精神分裂症行为模型中，zj43的一种单酯前药比母药zj43的活性高约7倍。这些发现鼓励我们进一步研究NAAG肽酶抑制剂的前药设计、合成和药理研究。通过SBIR I期资助，我们打算将NAAG肽酶抑制剂在精神分裂症动物模型中的疗效提升到更高的临床前开发水平，并最终促进将这一概念转化为临床试验。具体目标1：化合物的合成：合理设计和合成新的NAAG肽酶抑制剂的前药形式。基于我们的NAAG肽酶抑制剂的结构和一些商业前药的成功结果，我们将合成目前最佳候选药物ZJ 43、ZJ 11和ZJ 17的单酯和-酰胺前药13种前药，用于Aim 2中描述的测试。同时制备NAAG肽酶抑制剂zj43、zj11、zj17各1.0 g作为参比化合物，用于前药研究的疗效比较。特异性目标2：表征上述NAAG肽酶抑制剂的前药在体内的疗效，包括pcp诱导的精神分裂症行为模型（目标2.1）；对于行为上最有效的前药：定义它们在体内产生的NAAG肽酶抑制水平（Aim 2.2）；直接测量大脑中前药和活性抑制剂的水平（Aim 2.3）；确定前药是否具有肽酶抑制剂或II组mGluR激动剂的固有活性（Aim 2.4）。公共卫生相关性：精神分裂症是一种慢性、严重和致残的脑部疾病。通过这项为期两年的SBIR I期资助，我们打算将NAAG肽酶抑制剂及其新型前药在精神分裂症动物模型中的疗效提升到更高的临床前开发水平，并最终促进将这一概念转化为精神分裂症治疗的临床试验。

DESCRIPTION (provided by applicant): Schizophrenia is a chronic, severe, and disabling brain disease. Nearly 1 percent of the population develops schizophrenia during their lifetime - more than 2 million Americans suffer from this disease in a given year. The schizophrenia world market generated total revenues of nearly $12 billion in 2004 and is still growing steadily. Atypical antipsychotic drugs, such as clozapine, risperidone, and olanzapine are widely used to treat schizophrenia but are not fully effective in moderating the positive, negative and cognitive symptoms that different patients present. These drugs act primarily via antagonism of dopamine and serotonin receptors. However, a substantial literature supports the involvement of glutamatergic circuits in mediating the symptoms of schizophrenia in humans and animal models of this disorder. As a result, glutamate receptor ligands are under active analysis as potential alternative and adjuvant therapy for the treatment of this disorder. Among these are activators of the glycine site on the NMDA receptor and group II metabotropic glutamate receptor (mGluR) agonists. N-Acetylaspartylglutamate (NAAG) is the third most prevalent transmitter in the mammalian nervous system and a group II mGluR (mGluR3>>mGluR2) selective agonist. It is inactivated by extracellular peptidases (GCPII and III) to N-acetylaspartate (NAA) and glutamate (Glu) following the release of the peptide into the synaptic space. Inhibition of GCPII and III increases NAAG levels with the consequent activation of presynaptic group II mGluRs. Group II mGluR activation inhibits the release of glutamate and reduces the schizophrenia-like behavioral symptoms elicited by phencyclidine (PCP). Our research team demonstrated that NAAG peptidase inhibition and subsequent group II mGluR activation by NAAG also reduces these behaviors and thus potentially represents a new therapeutic approach to schizophrenia and acute PCP intoxication. After extensive SAR studies, our research team has identified a number of urea-based compounds, including ZJ 43, ZJ 11 and ZJ 17, as NAAG peptidase inhibitors with nanomolar potency. Systemic administration of the NAAG peptidase inhibitor ZJ 43 reduces PCP-induced behaviors in a rat model of schizophrenia, and this action of ZJ 43 is blocked by the group II mGluR antagonist LY341495. However, there exists an important concern that these compounds are too polar to readily penetrate the blood-brain barrier (BBB) and to advance to human clinical studies. The development of prodrugs will provide the means for precise dose delivery to the brain to improve their efficacy as well as the use of lower dose ranges that obviate the problem of unwanted systemic side effects. The long-term goal of this research project is to develop these NAAG peptidase inhibitors as novel therapeutics or adjuvant therapies for schizophrenia. In order to accelerate the development and application of these compounds for human clinical trials, the immediate goal of this research proposal is to develop novel prodrugs to improve the BBB penetration capabilities of our candidate NAAG peptidase inhibitors to improve their efficacy. It is noteworthy that our very recent preliminary data have demonstrated that one mono-ester prodrug of ZJ 43 is about 7-fold more active than the parent drug ZJ 43 in our PCP-induced behavioral model of schizophrenia. These findings encouraged us to pursue further studies on the design, synthesis and pharmacological investigation of prodrugs of our NAAG peptidase inhibitors. Through funding from this SBIR Phase I grant, we intend to bring our discovery of the efficacy of NAAG peptidase inhibitors in animal models of schizophrenia to a higher level of preclinical development and ultimately to foster the translation of this concept into clinical trials. Specific Aim 1: Synthesis of compounds: Rational design and synthesis of new prodrug forms of lead NAAG peptidase inhibitors. Based upon the structures of our NAAG peptidase inhibitors and the successful results achieved for some commercial prodrugs, thirteen prodrugs including mono-ester and -amide prodrugs of the current best drug candidates ZJ 43, ZJ 11, and ZJ 17 will be synthesized for the testing described in Aim 2. In addition, 1.0 gram each of the NAAG peptidase inhibtors ZJ 43, ZJ 11, and ZJ 17 will be prepared as reference compounds for the purpose of efficacy comparison during the studies of their prodrugs. Specific Aim 2: Characterization of the efficacy of the above prodrugs of NAAG peptidase inhibitors in vivo, including PCP-induced behavioral models of schizophrenia (Aim 2.1); For the behaviorally most effective prodrugs: definition of the level of NAAG peptidase inhibition that they produce in vivo (Aim 2.2); Direct measurement of the levels of the prodrugs and active inhibitors in the brain (Aim 2.3); Determination if the prodrugs have any inherent activity as peptidase inhibitors or group II mGluR agonists (Aim 2.4). PUBLIC HEALTH RELEVANCE: Schizophrenia is a chronic, severe, and disabling brain disease. Through funding from this two-year SBIR Phase I grant, we intend to bring our discovery of the efficacy of NAAG peptidase inhibitors and their novel prodrugs in animal models of schizophrenia to a higher level of preclinical development and ultimately to foster the translation of this concept into clinical trials for the treatment of schizophrenia.