Optimization of Small Molecule GPR17 Antagonists for Multiple Sclerosis

多发性硬化症小分子 GPR17 拮抗剂的优化

基本信息

批准号：
10369692
负责人：
Sanju Narayanan
金额：
$ 10.97万
依托单位：
RESEARCH TRIANGLE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10369692
关键词：
Ablation Adverse effects Agonist Autoimmune Biological Assay Biology Brain Cell Differentiation process Chemistry Chronic Collaborations Complement Computer Analysis Data Demyelinating Diseases Demyelinations Dendrites Development Disease Disease Progression Ensure Evaluation Exhibits Experimental Autoimmune Encephalomyelitis Financial compensation Frequencies G-Protein-Coupled Receptors GPR17 gene Goals Homology Modeling Immune response Immunomodulators Immunosuppressive Agents Impairment In Vitro Ion Channel Knockout Mice Lead Ligands Literature Mediating Metabolic Modeling Modification Multiple Sclerosis Mus Myelin Myelin Basic Proteins Myelin Sheath National Institute of Mental Health Neural Conduction Neurologic Neurons Oligodendroglia Orphan Peripheral Permeability Pharmaceutical Preparations Pharmacology Pharmacology Study Pharmacotherapy Play Process Property Psychotropic Drugs Rattus Relapse Reporting Role Series Severities Signal Transduction Solubility System Techniques Therapeutic Up-Regulation Validation Work analog antagonist axonal degeneration base blood-brain barrier permeabilization design disability drug discovery improved in silico in vivo mouse model myelination nervous system disorder new therapeutic target novel novel therapeutics oligodendrocyte precursor overexpression pharmacophore precursor cell programs receptor release of sequestered calcium ion into cytoplasm remyelination repaired scaffold screening program small molecule therapeutic target tool

Ablation Adverse effects Agonist Autoimmune Biological Assay Biology Brain Cell Differentiation process Chemistry Chronic Collaborations Complement Computer Analysis Data Demyelinating Diseases Demyelinations Dendrites Development Disease Disease Progression Ensure Evaluation Exhibits Experimental Autoimmune Encephalomyelitis Financial compensation Frequencies G-Protein-Coupled Receptors GPR17 gene Goals Homology Modeling Immune response Immunomodulators Immunosuppressive Agents Impairment In Vitro Ion Channel Knockout Mice Lead Ligands Literature Mediating Metabolic Modeling Modification Multiple Sclerosis Mus Myelin Myelin Basic Proteins Myelin Sheath National Institute of Mental Health Neural Conduction Neurologic Neurons Oligodendroglia Orphan Peripheral Permeability Pharmaceutical Preparations Pharmacology Pharmacology Study Pharmacotherapy Play Process Property Psychotropic Drugs Rattus Relapse Reporting Role Series Severities Signal Transduction Solubility System Techniques Therapeutic Up-Regulation Validation Work analog antagonist axonal degeneration base blood-brain barrier permeabilization design disability drug discovery improved in silico in vivo mouse model myelination nervous system disorder new therapeutic target novel novel therapeutics oligodendrocyte precursor overexpression pharmacophore precursor cell programs receptor release of sequestered calcium ion into cytoplasm remyelination repaired scaffold screening program small molecule therapeutic target tool

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项目摘要

Project Summary: The goal of this R03 proposal is to develop potent, selective antagonists for the orphan receptor GPR17. Ultimately, ligands developed under this application will serve as tools to probe signaling mechanisms and in vivo functions, and could expedite development of novel therapies for diseases potentially mediated by GPR17, such as Multiple Sclerosis (MS). MS is a severe neurological disease characterized by autoimmune-mediated demyelination of neurons and oligodendrocyte damage. The resulting axonal degeneration impairs rapid nerve conduction, which leads to neurological disability if not repaired through remyelination. The remyelination process requires proliferation and maturation of oligodendrocyte precursor cells (OPCs) into myelin producing mature oligodendrocytes. GPR17 is an orphan GPCR that has been identified as a negative regulator of oligodendrocyte maturation and is predominantly expressed in OPCs. GPR17-/- mice have increased CNS myelination and GPR17 overexpressing mice showed lack of myelin sheath formation in the CNS, similar to that seen in myelinating disorders. Addition of the GPR17 agonist probe MDL29,951 to cultures from GPR17+/- mice resulted in reduced differentiation of oligodendrocytes, along with a decrease in myelin basic protein (MBP) and dendrite formation. In addition, studies using an MS mouse model (experimental autoimmune encephalomyelitis, EAE) showed an upregulation of GPR17 in CNS regions where demyelination was occurring. Collectively, these data suggest the involvement of GPR17 in CNS demyelination upon activation. Hence, novel small molecule antagonists that can selectively modulate GPR17 functions will be invaluable tools to study GPR17 biology and lead to new drug discovery opportunities to treat severe demyelinating diseases such as MS. To date, very few small molecule antagonists have been reported in the literature and pharmacological studies with the existing non-selective and less potent antagonists have been challenging. Our preliminary work led to the identification of a novel small molecule lead compound SN-50 (GPR17 IC50 = 1701 nM, CysLT1, IC50 = 6580 nM) through structural modification of Pranlukast, a non-selective GPR17 antagonist (GPR17 IC50 = 588 nM, CysLT1 IC50 = 4 nM). SN-50 exhibited ~3- and 1600-fold reduced potency at GPR17 and CysLT1 respectively, and is ~4-fold selective for GPR17 over CysLT1. Moreover, SN-50 exhibits ~6-fold improved selectivity compared to our previous lead SN-23 (GPR17 IC50 = 1035 nM, CysLT1, IC50 = 590 nM), which promoted oligodendrocyte differentiation upon evaluation in a rat OPC differentiation assay. SN-50 therefore serves as an excellent lead to identify potent and selective GPR17 antagonists. In Specific Aim 1 of the proposed R03 project, we will synthesize at least 100 novel SN-50 analogs through a series of iterative scaffold modifications. In Specific Aim 2, we will evaluate the synthesized compounds for GPR17 potency and selectivity over CysLT1. Preliminary ADME properties of two lead compounds with favorable antagonist potency and selectivity (GPR17 IC50 < 100 nM, >50-fold selectivity over CysLT1) will also be evaluated. These Aims will be accomplished through a collaboration of chemistry and in vitro pharmacology.

项目摘要：该R03提案的目标是为孤儿发展有力的选择性对手受体GPR17。最终，在此应用程序下开发的配体将作为探测信号传导的工具机制和体内功能，可以加快对疾病的新疗法的发展由GPR17介导，例如多发性硬化症（MS）。 MS是一种严重的神经系统疾病，其特征是自身免疫性介导的神经元和少突胶质细胞损伤的脱髓鞘。产生的轴突退化会损害快速神经传导，如果不修复，会导致神经残疾再髓。透明过程需要少突胶质细胞前体细胞增殖和成熟（OPC）进入产生成熟的少突胶质细胞的髓磷脂。 GPR17是孤儿GPCR，已被确定为少突胶质细胞成熟的负调节剂，主要在OPC中表达。 GPR17 - / - 鼠有 CNS髓鞘升高和GPR17过表达的小鼠显示出缺乏髓鞘形成中枢神经系统，类似于在髓鞘疾病中看到的中枢神经系统。将GPR17激动剂探针MDL29,951添加到培养物中从GPR17 +/-小鼠中导致少突胶质细胞的分化减少，并且髓磷脂碱性降低蛋白质（MBP）和树突形成。此外，使用MS小鼠模型的研究（实验自身免疫脑脊髓炎，EAE）在发生脱髓鞘的中枢神经系统区域显示了GPR17的上调。总的来说，这些数据表明GPR17在激活后参与中枢神经系统脱髓鞘。因此，新颖可以选择性调节GPR17功能的小分子拮抗剂将是研究的宝贵工具 GPR17生物学并带来新的药物发现机会，以治疗严重的脱髓鞘疾病，例如多发性硬化症。迄今为止，文献和药理学中有很少的小分子拮抗剂。与现有的非选择性和较低有效的拮抗剂的研究一直具有挑战性。我们的初步工作导致新型小分子铅化合物SN-50（GPR17 IC50 = 1701 nm，Cyslt1，IC50）的鉴定 = 6580 nm）通过pranlukast的结构修饰，一种非选择性GPR17拮抗剂（GPR17 IC50 = 588） NM，Cyslt1 IC50 = 4 nm）。 SN-50在GPR17和CYSLT1时表现出〜3-和1600倍的效力对于cyslt1而言，GPR17的选择性分别为〜4倍。此外，SN-50展品提高了6倍与我们以前的铅SN-23（GPR17 IC50 = 1035 nm，cyslt1，ic50 = 590 nm）相比，选择性大鼠OPC分化测定法评估后，促进了少突胶质细胞分化。因此，SN-50 是识别有效和选择性GPR17拮抗剂的出色领导。在拟议的特定目标1中 R03项目，我们将通过一系列迭代脚手架综合至少100个新型SN-50类似物修改。在特定目标2中，我们将评估GPR17效力和选择性的合成化合物超过cyslt1。具有良好拮抗剂效力的两种铅化合物的初步ADME特性和还将评估选择性（GPR17 IC50 <100 nm，> cyslt1的50倍选择性）。这些目标将是通过化学和体外药理学的合作完成。