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

• 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
• 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

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：R03 提案的目标是为孤儿开发有效的、选择性的拮抗剂 受体GPR17。最终，在此应用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，并可能加速疾病新疗法的开发 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 自身免疫介导的神经元脱髓鞘和少突胶质细胞损伤。由此产生的轴突 退化会损害快速神经传导，如果不通过修复修复，会导致神经功能障碍 髓鞘再生。髓鞘再生过程需要少突胶质前体细胞的增殖和成熟 (OPC) 进入产生髓磷脂的成熟少突胶质细胞。 GPR17 是一个孤儿 GPCR，已被鉴定为 少突胶质细胞成熟的负调节因子，主要在 OPC 中表达。 GPR17-/- 小鼠有 中枢神经系统髓鞘形成增加和 GPR17 过表达小鼠的髓鞘形成缺乏 中枢神经系统，类似于髓鞘疾病。将 GPR17 激动剂探针 MDL29,951 添加到培养物中 来自 GPR17+/- 小鼠的结果导致少突胶质细胞分化减少，同时髓磷脂碱性减少 蛋白质（MBP）和树突形成。此外，使用 MS 小鼠模型（实验性自身免疫 脑脊髓炎（EAE）显示，在发生脱髓鞘的中枢神经系统区域，GPR17 表达上调。 总的来说，这些数据表明 GPR17 激活后参与中枢神经系统脱髓鞘。因此，小说 能够选择性调节 GPR17 功能的小分子拮抗剂将成为宝贵的研究工具 GPR17 生物学并带来治疗严重脱髓鞘疾病的新药物发现机会，例如 多发性硬化症。 迄今为止，小分子拮抗剂的文献报道和药理学报道还很少。 对现有非选择性且效力较低的拮抗剂的研究一直具有挑战性。我们的前期工作 导致鉴定出一种新型小分子先导化合物 SN-50 (GPR17 IC50 = 1701 nM, CysLT1, IC50 = 6580 nM) 通过普仑司特（一种非选择性 GPR17 拮抗剂）的结构修饰 (GPR17 IC50 = 588 nM，CysLT1 IC50 = 4 nM）。 SN-50 对 GPR17 和 CysLT1 的效力分别降低了约 3 倍和 1600 倍 分别对 GPR17 的选择性是 CysLT1 的约 4 倍。此外，SN-50 的性能提高了约 6 倍 与我们之前的先导 SN-23 (GPR17 IC50 = 1035 nM, CysLT1, IC50 = 590 nM) 相比，选择性更高 在大鼠 OPC 分化测定中进行评估后，促进少突胶质细胞分化。因此SN-50 是鉴定有效且选择性 GPR17 拮抗剂的极好先导。在拟议的具体目标 1 中 R03项目，我们将通过一系列迭代支架合成至少100个新颖的SN-50类似物 修改。在具体目标 2 中，我们将评估合成化合物的 GPR17 效力和选择性 超过 CysLT1。两种具有良好拮抗效力的先导化合物的初步 ADME 特性 还将评估选择性（GPR17 IC50 < 100 nM，选择性比 CysLT1 高 50 倍）。这些目标将是 通过化学和体外药理学的合作完成。