Therapeutic Strategy for NASH

NASH 的治疗策略

• 批准号: 10323904
• 负责人: HERBERT H SELTZMAN
• 金额: $ 25.65万
• 依托单位: ARTIAM BIO INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323904
• 关键词: Adverse effects; Agonist; Alcoholic Liver Diseases; American; Anhedonia; Anti-Obesity Agents; Behavior assessment; Behavioral; Benign; Binding Proteins; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Body Weight decreased; Brain; Brain region; CB1 receptor antagonist; CNR1 gene; Cardiovascular system; Characteristics; Chronic; Clinical; Cognitive; Comparative Study; Consumption; Coupled; Cytochrome P450; Data; Development; Diet; Disease; Dose; Drug Kinetics; Emotional; Enzymes; Europe; FDA approved; Fatty Liver; Generations; Goals; Hepatic; Human; Lead; Legal patent; Ligands; Lipids; Liver diseases; Metabolic syndrome; Modeling; Neuraxis; New Agents; Non-Rodent Model; Obesity; Oral; Organ; Outcome; Patients; Penetration; Peripheral; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Plasma Proteins; Process; Property; Rattus; Regimen; Resolution; Risk; Rodent; SR 141716A; Safety; Severities; Solubility; Sucrose; Testing; Therapeutic; Time; Tissues; Water; Withdrawal; absorption; base; behavior test; clinical development; clinically relevant; design; diet-induced obesity; dysphoria; efficacy study; efficacy testing; endocannabinoid signaling; endogenous cannabinoid system; exhibitions; fatty acid oxidation; forced swim test; improved; in vivo evaluation; insulin sensitivity; islet amyloid polypeptide; lead candidate; lipid biosynthesis; lipid metabolism; liver development; non-alcoholic fatty liver disease; non-drug; nonalcoholic steatohepatitis; novel; novel therapeutics; pre-clinical; receptor; reward processing; rimonabant; screening

Abstract: Therapeutic Strategy for NASH The overall goal of this project is to identify for clinical development a peripherally selective neutral antagonist of the CB1 receptor for non-alcoholic steatohepatitis (NASH). Non-alcoholic fatty liver disease (NAFLD) associated with metabolic syndrome (MetS) can progress to NASH, which is a serious disease without an FDA- approved drug. There is a strong correlation between severity of NAFLD and development of NASH, which indicate that decreasing fatty liver (steatosis) is a legitimate strategy for NASH. Compounds that antagonize the CB1 receptor provide many benefits in MetS through both central nervous system (CNS) and peripheral mechanisms. Importantly, resolution of NAFLD is achievable by targeting hepatic CB1 receptors, thereby decreasing de novo lipogenesis and increasing fatty acid oxidation. Competitive orthosteric antagonists can be either inverse agonists that block basal receptor activity or neutral/silent antagonists that are devoid of this effect. Previous attempts to target CB1 using inverse agonists led to psychiatric adverse effects in some patients as the CB1 receptor is involved in reward processing within the CNS. Suppression of basal receptor activity possibly caused exacerbation of dysphoric effects. Presently, efforts are underway to produce CNS-sparing inverse agonists to target peripheral CB1 receptors. However, a complicating factor with this strategy is that the blood-brain barrier that protects the brain is not continuous and chronic use of peripheral inverse agonists still has the possibility of producing adverse effects. Artiam Bio has produced neutral antagonists of the CB1 receptor with limited brain penetration. These compounds have the dual advantage of reduced brain penetration coupled with lack of suppressive effects on basal receptor activity. This approach represents a much-improved strategy for targeting the CB1 receptor for NASH and other important diseases. Three aims are proposed: (1) ADMET characterization of the ligands, off-target receptor screening and pharmacokinetic profiling. (2) Establish efficacy by testing Artiam's best compound in a diet-induced model of NASH that is relevant to the human condition. (3) Behavioral testing of the lead candidate in two different assays using a chronic dosing regimen to establish an acceptable safety profile compared to a classical inverse agonist of CB1. Successful completion of these studies will lead to identification of a first in class, behaviorally de-risked, clinical development candidate for NASH targeting the CB1 receptor.

摘要：NASH的治疗策略 该项目的总体目标是确定用于临床开发的外周选择性中性拮抗剂 非酒精性脂肪性肝炎（NASH）的CB 1受体。非酒精性脂肪肝（NAFLD） 与代谢综合征（MetS）相关的疾病可能进展为NASH，这是一种没有FDA批准的严重疾病。 批准的药物。NAFLD的严重程度与NASH的发展之间存在密切相关性，这 表明减少脂肪肝（脂肪变性）是NASH的合理策略。拮抗药物的化合物 CB 1受体通过中枢神经系统（CNS）和外周神经系统在MetS中提供许多益处 机制等重要的是，NAFLD的消退可以通过靶向肝CB 1受体来实现， 减少从头脂肪生成和增加脂肪酸氧化。竞争性正构拮抗剂可以是 阻断基础受体活性的反向激动剂或缺乏这种活性的中性/沉默拮抗剂 效果以前尝试使用反向激动剂靶向CB 1导致一些患者的精神不良反应 因为CB 1受体参与中枢神经系统内的奖赏处理。基础受体活性抑制 可能导致烦躁症状加重目前，正在努力生产保留CNS的 靶向外周CB 1受体的反向激动剂。然而，这一战略的一个复杂因素是， 保护大脑的血脑屏障不连续，外周反向激动剂仍长期使用 有可能产生不良影响。Artiam Bio生产了CB 1受体的中性拮抗剂 大脑穿透力有限这些化合物具有减少脑渗透的双重优点， 对基础受体活性缺乏抑制作用。这种方法是一种改进了很多的战略 针对NASH和其他重要疾病的CB 1受体。提出了三个目标：（1）ADMET 配体的表征、脱靶受体筛选和药代动力学分析。(2)确立疗效 通过在饮食诱导的NASH模型中测试Artiam的最佳化合物，该模型与人类状况相关。（三） 在两种不同的试验中使用慢性给药方案对先导候选物进行行为测试，以建立 与CB 1的经典反向激动剂相比，具有可接受的安全性特征。成功完成这些研究 将导致确定NASH的一流的、行为风险降低的临床开发候选药物 针对CB 1受体。