Novel therapeutic approach for NASH

NASH 的新治疗方法

• 批准号: 10179374
• 负责人: RANGAN MAITRA
• 金额: $ 51.8万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-04 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10179374
• 关键词: 2-arachidonylglycerol; Adipose tissue; Adverse effects; Agonist; American; Anti-Inflammatory Agents; Antiinflammatory Effect; Appetite Stimulants; Behavior; Behavioral; Binding; Biological Assay; Biological Markers; Brain; CNR1 gene; CNR2 gene; Cannabinoids; Catalepsy; Cells; Cholesterol; Development; Diet; Disease; Drug Kinetics; Endocannabinoids; Evaluation; Fatty Liver; Fatty acid glycerol esters; Goals; Hepatic; Hepatocyte; Histologic; Immune; In Vitro; Indazoles; Inflammation; Lead; Ligands; Lipids; Liver; Liver diseases; Marijuana; Metabolic; Methionine; Modeling; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; PET/CT scan; Pancreas; Penetration; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Property; Pyrazoles; Reporting; Research; Signal Transduction; Skeletal Muscle; Testing; Tetrahydrocannabinol; Tissues; United States; anandamide; beta-arrestin; cannabinoid receptor; choline deficient diet; clinical development; design; efficacy evaluation; efficacy study; efficacy testing; epidemiologic data; epidemiology study; feeding; immune activation; innovation; islet amyloid polypeptide; liver injury; liver transplantation; marijuana use; marijuana user; natural hypothermia; nonalcoholic steatohepatitis; novel strategies; novel therapeutic intervention; overexpression; radioligand; receptor; recruit; release of sequestered calcium ion into cytoplasm; scaffold; side effect; sugar

The overall goal of this project is to develop peripherally restricted partial agonists of the cannabinoid receptors (CB1 and CB2) for the treatment of non-alcoholic steatohepatitis (NASH). These compounds are expected to mimic the peripheral effects of THC ((−)-trans-Δ⁹-tetrahydrocannabinol), the only known orthosteric ligand of the CB receptors in marijuana while avoiding adverse CNS related side-effects. There are two known cannabinoid receptors – CB1 and CB2. The CB1 receptor is highly expressed on neurons of the CNS along with certain peripheral organs like the liver, pancreas, skeletal muscle and adipose tissue. The CB2 receptor is mostly expressed on immune cells Epidemiological studies indicate that marijuana users have reduced rates of NASH, type 2 diabetes and obesity. These contrarian effects are in sharp contrast to known orexigenic effects of marijuana via the CNS. These observations can be explained by disparate pharmacological effects of THC – a partial agonist. A partial agonist can act like a traditional agonist when excess receptors are present. However, a partial agonist can also act as a functional antagonist when number of receptors is limited by competing with a full agonist and by reducing downstream signaling. In the injured liver, the expression of CB1 is low to moderate but there is a large influx of CB2 expressing immune cells. Further, expression of the full agonist endocannabinoid 2-AG is ~1000-fold higher than that of the partial agonist AEA. We hypothesized that in NASH a partial agonist might be able to reduce fatty liver via functional antagonism of CB1 while producing anti- inflammatory effects by targeting CB2. We successfully tested this hypothesis using a well characterized partial agonist of CB receptors and an early lead compound in a model of NASH. Continuation of our preliminary studies is proposed through 3 integrated specific aims: (1) Synthesize partial CB receptor agonists that are peripherally restricted. We have started to explore a primary indazole scaffold and a secondary pyrazole scaffold to produce partial agonists of CB receptors that have limited CNS penetration. Continued refinement of early leads will lead to compounds with optimized drug-like properties. (2) Perform pharmacological characterization using various functional and binding assays and ADMET profiling of synthesized compounds to identify promising leads. Select compounds will undergo pharmacokinetic evaluation and behavioral profiling to rule out CNS-effects. (3) Perform efficacy testing in NASH models. We propose to evaluate our most promising leads in models of NASH for efficacy. In tandem, we will assess various biomarkers of efficacy and perform receptor occupancy studies to identify an optimized mature lead and two backups for further development.

该项目的总体目标是开发外周受限的大麻素受体部分激动剂。 (CB1和CB2)用于治疗非酒精性脂肪性肝炎(NASH)。这些化合物预计会 模拟四氢大麻酚((−)-反式-Δ⁹-四氢大麻酚)的外周效应，这是已知的唯一的正构体配体 减少大麻中的CB受体，同时避免与中枢神经系统相关的不良反应。有两种已知的大麻素 受体-CB1和CB2。CB1受体在中枢神经系统神经元上高表达，并与某些 外周器官，如肝脏、胰腺、骨骼肌和脂肪组织。CB2受体主要是 表达在免疫细胞上的流行病学研究表明，吸食大麻的人患NASH的几率降低， 2型糖尿病和肥胖症。这些反向效应与已知的促食欲效应形成鲜明对比 大麻通过中枢神经系统。这些观察结果可以用THC-a不同的药理作用来解释。 部分激动剂。当存在过量受体时，部分激动剂可以起到传统激动剂的作用。然而，a 部分激动剂也可以作为功能拮抗剂，当受体的数量受到竞争时 全激动剂和减少下游信号转导。在损伤的肝脏中，CB1的表达为低到中等 但有大量表达CB2的免疫细胞涌入。此外，完整激动剂的表达 内源性大麻素2-AG是部分激动剂AEA的1000倍。我们假设在纳什 部分激动剂可能通过对CB1的功能性拮抗而减轻脂肪肝，同时产生抗 靶向CB2的炎症效应。我们成功地测试了这一假设，使用了一个具有良好特征的部分 CB受体激动剂和NASH模型中的早期先导化合物。继续我们的初步研究 通过3个综合的具体目标提出：(1)合成外围的部分CB受体激动剂 有限制。我们已经开始探索一次吲唑支架和二次吡唑支架来生产 CB受体的部分激动剂，限制了中枢神经系统的穿透。继续完善早期销售线索将带来 到具有优化的类药物特性的化合物。(2)使用不同的方法进行药理表征 对合成化合物进行功能性和结合性分析以及ADMET分析，以确定有希望的线索。 选定的化合物将接受药代动力学评估和行为分析，以排除中枢神经系统的影响。(3) 在NASH模型中执行有效性测试。我们建议评估我们在NASH模型中最有希望的线索 以求疗效。同时，我们将评估各种有效的生物标记物，并进行受体占有率研究 确定一个经过优化的成熟销售线索和两个备份以供进一步开发。