Novel therapeutic approach for NASH

NASH 的新治疗方法

• 批准号: 10616609
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10616609
• 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; Disparate; Drug Kinetics; Early identification; 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; Muscle; 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; antagonist; antinociception; beta-arrestin; cannabinoid receptor; choline deficient diet; clinical development; design; efficacy evaluation; efficacy study; efficacy testing; epidemiologic data; epidemiology study; feeding; innovation; islet amyloid polypeptide; liver injury; liver transplantation; marijuana use; marijuana user; natural hypothermia; nonalcoholic steatohepatitis; novel strategies; novel therapeutic intervention; overexpression; pharmacologic; radioligand; receptor; recruit; release of sequestered calcium ion into cytoplasm; scaffold; side effect; skeletal tissue; 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大麻素受体的外周限制性部分激动剂 (CB1和CB 2）用于治疗非酒精性脂肪性肝炎（NASH）。这些化合物预期 模拟THC（（-）-反式-Δ ε-四氢大麻酚）的外周效应，THC是唯一已知的 大麻中的CB受体，同时避免不利的CNS相关副作用。有两种已知的大麻素 受体-CB 1和CB 2。CB 1受体在CNS的神经元上高度表达，沿着某些 外周器官如肝脏、胰腺、骨骼肌和脂肪组织。CB 2受体主要是 在免疫细胞上表达流行病学研究表明大麻使用者降低了NASH的发病率， 2型糖尿病和肥胖。这些相反的效果与已知的 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，部分激动剂可以像传统激动剂一样起作用。但 部分激动剂也可以作为功能性拮抗剂，当受体的数量受到限制时， 完全激动剂和减少下游信号传导。在损伤的肝脏中，CB 1的表达为低至中度 但有大量表达CB 2的免疫细胞流入。此外，完全激动剂的表达 内源性大麻素2-AG比部分激动剂AEA高约1000倍。我们假设在NASH中 部分激动剂可能能够通过CB 1的功能性拮抗作用减少脂肪肝，同时产生抗- 通过靶向CB 2的炎症作用。我们成功地测试了这一假设，使用一个良好的特点部分 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个整合的具体目标提出：（1）合成外周的部分CB受体激动剂， 限制。我们已经开始探索一级吲唑支架和二级吡唑支架， CB受体的部分激动剂具有有限的CNS渗透。继续完善早期线索将导致 到具有优化的药物样性质的化合物。(2)使用各种药物进行药理学表征 合成化合物的功能和结合分析以及ADMET分析，以鉴定有希望的先导化合物。 选择的化合物将进行药代动力学评价和行为分析，以排除CNS效应。（三） 在NASH模型中进行有效性测试。我们建议在NASH模型中评估我们最有前途的线索 为了有效性。同时，我们将评估各种有效性生物标志物，并进行受体结合研究， 确定一个优化的成熟线索和两个备用线索，以便进一步开发。

项目成果

Discovery of 1,3-disubstituted pyrazole peripheral cannabinoid receptor partial agonists.

1,3-二取代吡唑外周大麻素受体部分激动剂的发现。

• DOI: 10.1016/j.bmcl.2023.129430
• 发表时间: 2023
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Amato,George;Runyon,Scott;Vasukuttan,Vineetha;Decker,AnnM;Gay,ElaineA;Laudermilk,Lucas;Maitra,Rangan
• 通讯作者: Maitra,Rangan

Structure-Activity Relationship Development Efforts towards Peripherally Selective Analogs of the Cannabinoid Receptor Partial Agonist BAY 59-3074.

• DOI: 10.3390/molecules27175672
• 发表时间: 2022-09-02
• 期刊: Molecules (Basel, Switzerland)