Novel therapeutic approach for NASH

NASH 的新治疗方法

基本信息

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
项目类别：
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

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大麻素受体的外围局部局部激动剂（CB1和CB2）用于治疗非酒精性脂肪性肝炎（NASH）。这些化合物有望模仿Thc（（ - ） - trans-Δ⁹四氢大麻醇）的外围作用，这是唯一已知的正常配体大麻中的CB接收器，同时避免了与中枢神经系统相关的不良副作用。有两个已知的大麻素受体 - CB1和CB2。 CB1受体高度表达在CNS的神经元上外围器官，例如肝脏，胰腺，骨骼肌和脂肪组织。 CB2受体主要是在免疫细胞的流行病学研究表明，大麻使用者的纳什率降低了， 2型糖尿病和肥胖症。这些对比效应与已知的培训作用形成鲜明对比大麻通过中枢神经系统。这些观察结果可以通过THC的不同药物效应来解释部分激动剂。当存在超过受体时，部分激动剂可以像传统的激动剂一样起作用。但是，当接收者数量通过与A竞争限制时，部分激动剂也可以充当功能对手全部激动剂，并通过减少下游信号传导。在受伤的肝脏中，CB1的表达低至现代但是CB2表达免疫细胞的影响很大。此外，表达完整的激动剂内源性大麻素2-AG比部分激动剂AEA高约1000倍。我们假设在纳什部分激动剂可能能够通过CB1的功能拮抗作用来减少脂肪肝通过靶向CB2，炎症作用。我们使用良好的部分表征成功地检验了这一假设 CB受体的激动剂和NASH模型中的早期铅化合物。继续我们的初步研究通过3个集成的特定目的提出：（1）综合外周的部分CB受体激动剂受限制的。我们已经开始探索主要的吲哚唑支架和次要吡唑脚手架来生产 CB接收器的部分激动剂的渗透率有限。持续改进早期铅将导致具有具有优化药物样特性的化合物。（2）使用各种合成化合物的功能和结合测定和助力分析以识别有希望的铅。精选化合物将接受药代动力学评估和行为分析，以排除CNS效应。（3）在NASH模型中进行效率测试。我们建议在NASH模型中评估我们最有希望的线索提高效率。同时，我们将评估效率的各种生物标志物，并执行受体占用研究确定优化的成熟铅和两个备份以进行进一步发展。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.