Novel therapeutic approach for NASH

NASH 的新治疗方法

基本信息

批准号：
10426164
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
项目类别：
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/10426164
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 antagonist 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

项目摘要

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限制性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）。模拟 THC（(−)-trans-Δ⁹-四氢大麻酚）的外周效应，THC 是唯一已知的正构配体大麻中的 CB 受体，同时避免中枢神经系统相关的不良副作用有两种已知的大麻素。受体 – CB1 和 CB2 CB1 受体以及某些神经元在 CNS 神经元上高度表达。外周器官如肝脏、胰腺、骨骼肌和脂肪组织大多是CB2受体。流行病学研究表明，大麻使用者降低了 NASH 的发病率，这些逆向效应与 2 型糖尿病和肥胖症已知的促食欲效应形成鲜明对比。这些观察结果可以通过 THC 的不同药理作用来解释。当存在过量受体时，部分激动剂可以像传统激动剂一样发挥作用。当受体数量因与受体竞争而受到限制时，部分激动剂也可以充当功能性拮抗剂。完全激动剂并通过减少下游信号传导在受损的肝脏中，CB1 的表达为低至中度。但有大量表达 CB2 的免疫细胞涌入，此外，还表达了完全激动剂。内源性大麻素 2-AG 比部分激动剂 AEA 高约 1000 倍，我们在 NASH 中进行了研究。部分激动剂可能能够通过 CB1 的功能性拮抗作用来减少脂肪肝，同时产生抗- 通过靶向 CB2 的炎症效应，我们使用特征明确的部分成功测试了这一假设。 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。提出了 3 个综合的具体目标：（1）合成外周的部分 CB 受体激动剂我们已经开始探索生产初级吲唑支架和次级吡唑支架。限制中枢神经系统渗透的 CB 受体部分激动剂将导致早期先导药物的不断完善。具有优化的药物样特性的化合物 (2) 使用各种方法进行药理学表征。对合成化合物进行功能和结合测定以及 ADMET 分析，以识别有前景的先导化合物。选择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影响 (3)。我们建议评估 NASH 模型中最有前途的线索。同时，我们将评估各种功效生物标志物并进行受体占用研究确定一个优化的成熟领先优势和两个备用优势以供进一步开发。