Prodrugs of NAAG Peptidase Inhibitors for the Treatment of Schizophrenia

NAAG肽酶抑制剂的前药用于治疗精神分裂症

• 批准号: 7636774
• 负责人: David Anthony Lowe
• 金额: $ 30.05万
• 依托单位: PSYCHOGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-11 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7636774
• 关键词: Acids; Acute; Adjuvant Therapy; Adverse effects; Agonist; American; Amides; Amidohydrolases; Animal Model; Antipsychotic Agents; Area; Arizona; Arts; Back; Behavior; Behavioral; Behavioral Model; Behavioral Symptoms; Biological Assay; Blood - brain barrier anatomy; Brain; Brain Diseases; Chemistry; Chronic; Clinical Research; Clinical Treatment; Clinical Trials; Clozapine; Collaborations; Data; Development; Disease; Dopamine; Dose; Ensure; Esterification; Esters; Excitatory Amino Acid Antagonists; Fostering; Funding; Glutamate Carboxypeptidase II; Glutamate Receptor; Glutamates; Glycine; Goals; Grant; Hand; Housing; Human; Hydrolysis; In Vitro; Investigation; Laboratories; Laboratory Research; Lead; Leadership; Legal patent; Libraries; Licensing; Ligands; Literature; Marketing; Measurement; Mediating; Metabotropic Glutamate Receptors; Methods; Modeling; Molecular Models; Mono-S; Motor Activity; N-Methyl-D-Aspartate Receptors; N-acetylaspartate; N-acetylaspartylglutamate; Nature; Nervous system structure; Neuraxis; Neurobehavioral Manifestations; Neurologic; Neurotransmitters; Parents; Patients; Penetration; Peptide Hydrolases; Peptides; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phencyclidine; Population; Positioning Attribute; Process; Prodrugs; Protease Inhibitor; Protocols documentation; Rattus; Receptor Activation; Research; Research Project Grants; Research Proposals; Risperidone; Schizophrenia; Science; Senior Scientist; Site; Small Business Innovation Research Grant; Structure; Study Section; Symptoms; Synapses; Technology; Testing; Therapeutic; Translations; Universities; Urea; amidase; atypical antipsychotic; base; chemical synthesis; design; drug candidate; drug discovery; efficacy testing; esterase; experience; extracellular; follow-up; improved; in vivo; inhibitor/antagonist; metabotropic glutamate receptor 2; metabotropic glutamate receptor 3; molecular modeling; neurochemistry; novel; novel therapeutic intervention; novel therapeutics; olanzapine; phencyclidine intoxication; pre-clinical; presynaptic; professor; public health relevance; radiochemical; scale up; serotonin receptor

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.

描述（由申请人提供）：精神分裂症是一种慢性，严重且致残的脑部疾病。将近1％的人口在一生中发展出精神分裂症 - 在给定的一年中，超过200万美国人患有这种疾病。精神分裂症世界市场在2004年产生了近120亿美元的总收入，并且仍在稳步增长。非典型抗精神病药（例如氯氮平，利培酮和奥氮平）被广泛用于治疗精神分裂症，但在调节不同患者的正面，阴性和认知症状方面尚未完全有效。这些药物主要通过多巴胺和5-羟色胺受体的拮抗作用。但是，大量文献支持谷氨酸能回路参与介导人类和这种疾病动物模型中精神分裂症的症状。结果，谷氨酸受体配体正在积极分析，作为该疾病治疗的潜在替代和辅助治疗。其中包括NMDA受体上的甘氨酸位点的激活剂和II组代谢型谷氨酸受体（MGLUR）激动剂。 N-乙酰甲基谷氨酸（NAAG）是哺乳动物神经系统中第三大流行的发射器，而II组MGlur（mglur3 >> mglur2）选择性激动剂。在将肽释放到突触空间中后，它被细胞外肽酶（GCPII和III）灭活至N-乙酰天冬氨酸（NAA）和谷氨酸（GLU）。 GCPII和III的抑制作用随随之而来的突触前II MGLURS的激活增加了NAAG水平。 II组MGLUR激活抑制了谷氨酸的释放，并减少了苯基酮（PCP）引起的精神分裂症样行为症状。我们的研究小组表明，NAAG通过NAAG抑制NAAG肽酶抑制作用和随后的II组MGLUR激活也降低了这些行为，因此有可能代表一种用于精神分裂症和急性PCP中毒的新治疗方法。经过广泛的SAR研究，我们的研究团队确定了许多基于尿素的化合物，包括ZJ 43，ZJ 11和ZJ 17，为NaAg肽酶抑制剂具有纳摩尔效能。 NAAG肽酶抑制剂ZJ 43的全身给药可在精神分裂症的大鼠模型中降低PCP诱导的行为，而ZJ 43的这种作用被II组MGLUR拮抗剂LY341495阻止。然而，存在一个重要的担忧，即这些化合物太极了，无法轻易穿透血脑屏障（BBB）并促进人类的临床研究。前药的发展将为精确剂量递送到大脑以提高其功效以及使用较低剂量范围的方法，以消除不必要的全身副作用问题。该研究项目的长期目标是开发这些NAAG肽酶抑制剂，作为新型治疗剂或精神分裂症的辅助疗法。为了加速这些化合物在人类临床试验中的开发和应用，该研究建议的直接目标是开发新的前药，以提高我们候选的NAAG NAAG肽酶抑制剂的BBB渗透能力，以提高其效率。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，ZJ 43的一个单酯前药比母体药物ZJ 43高7倍。这些发现鼓励我们对NAAG肽酶抑制剂前药的设计，合成和药理研究进行进一步研究。通过这一SBIR I阶段赠款的资金，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高到更高水平的临床前开发，并最终将这种概念转化为临床试验。特定目的1：化合物的合成：铅NAAG肽酶抑制剂的新前药形式的合理设计和合成。基于我们NAAG肽酶抑制剂的结构以及一些商业前药取得的成功结果，包括当前最佳药物ZJ 43，ZJ 11和ZJ 17的13个前药，包括单酯和-AMIDE前药，还将在AIM 2中进行了ZJ JJ 11和ZJ 17的测试。 ZJ 17将作为参考化合物制备，以便在其前药研究期间进行功效比较。特定目标2：表征NaAg肽酶抑制剂体内的上述前药的功效，包括PCP诱导的精神分裂症行为模型（AIM 2.1）；对于行为上最有效的前药：它们在体内产生的NAAG肽酶抑制水平的定义（AIM 2.2）；直接测量大脑中的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激动剂的任何固有活性（AIM 2.4）。公共卫生相关性：精神分裂症是一种慢性，严重且致残的脑部疾病。通过这项为期两年的SBIR阶段I赠款的资金，我们打算将NAAG肽酶抑制剂及其在精神分裂症动物模型中的新型药物的疗效带入更高水平的临床前发展，并最终将这种概念转化为临床试验的临床试验，以治疗精神分裂症。