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.

项目概述：R 03提案的目标是为孤儿药开发有效的选择性拮抗剂。 GPR 17受体。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，并可能加快疾病的新疗法的开发， 由GPR 17介导的疾病，如多发性硬化症（MS）。MS是一种严重的神经系统疾病， 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 退化损害快速神经传导，如果不通过修复， 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 （OPCs）转化为产生髓鞘的成熟少突胶质细胞。GPR 17是一种孤儿GPCR，已被鉴定为 少突胶质细胞成熟的负调节因子，主要在OPCs中表达。GPR 17-/-小鼠具有 CNS髓鞘形成增加和GPR 17过表达的小鼠显示，在中枢神经系统中缺乏髓鞘形成。 CNS，类似于髓鞘形成疾病中所见。向培养物中添加GPR 17激动剂探针MDL 29，951 结果显示，GPR 17 +/-小鼠的神经胶质细胞分化减少，沿着髓鞘碱性磷酸酶的减少。 蛋白（MBP）和树突形成。此外，使用MS小鼠模型（实验性自身免疫）的研究 脑脊髓炎，EAE）显示在发生脱髓鞘的CNS区域中GPR 17的上调。 总的来说，这些数据表明GPR 17在活化后参与CNS脱髓鞘。因此，小说 可以选择性调节GPR 17功能的小分子拮抗剂将是研究的宝贵工具 GPR 17生物学和导致新药发现的机会，以治疗严重的脱髓鞘疾病， 女士 迄今为止，文献和药理学中报道的小分子拮抗剂很少 对现有的非选择性和效力较低的拮抗剂的研究具有挑战性。我们的前期工作 导致鉴定了新的小分子先导化合物SN-50（GPR 17 IC 50 = 1701 nM，CysLT 1，IC 50 = 6580 nM），通过非选择性GPR 17拮抗剂（GPR 17 IC 50 = 588 nM，CysLT1 IC50 = 4 nM）。SN-50在GPR 17和CysLT 1处表现出约3倍和1600倍的效价降低 并且对GPR 17的选择性是CysLT 1的约4倍。此外，SN-50表现出约6倍的改善， 与我们之前的先导SN-23（GPR 17 IC 50 = 1035 nM，CysLT 1，IC 50 = 590 nM）相比， 在大鼠OPC分化测定中评估时，促进少突胶质细胞分化。SN-50 作为鉴定有效的和选择性的GPR 17拮抗剂的极好的线索。具体目标1： R 03项目，我们将通过一系列迭代支架合成至少100种新型SN-50类似物 修改.在具体目标2中，我们将评价合成化合物的GPR 17效价和选择性 CysLT 1的具有良好拮抗剂效力的两种先导化合物的初步ADME性质， 还将评估选择性（GPR 17 IC 50 < 100 nM，超过CysLT 1的选择性>50倍）。这些目标将是 通过化学和体外药理学的合作完成。