Pregnane X Receptor (PXR) Antagonists for Non-Alcoholic Fatty Liver Disease

孕烷 X 受体 (PXR) 拮抗剂治疗非酒精性脂肪肝

• 批准号: 8905004
• 负责人: Jay Edward Wrobel
• 金额: $ 30万
• 依托单位: FOX CHASE CHEMICAL DIVERSITY CENTER, INC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8905004
• 关键词: Affect; Agonist; American; Animal Model; Antidiabetic Drugs; Applications Grants; Biological Assay; Caco-2 Cells; Chemicals; Chemistry; Cholesterol; Cirrhosis; Collaborations; Country; Data; Data Reporting; Diabetes Mellitus; Diet Modification; Disease; Disease model; Docking; Drug Kinetics; Estrogen Receptor alpha; Excretory function; Exercise; Fatty Liver; Fluorescence Resonance Energy Transfer; Foxes; Future; Genetic; Genetic Transcription; Goals; Half-Life; Hepatitis C; Hepatocyte; Human; In Vitro; Individual; Inhibitory Concentration 50; Laboratories; Lead; Ligand Binding; Ligands; Lipids; Liver diseases; Medicine; Metabolic; Metabolic syndrome; Metabolism; Microsomes; Midazolam; Modeling; Mus; Obesity; Oral Administration; PPAR gamma; Pathway interactions; Peer Review; Permeability; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Plasma Proteins; Population; Positioning Attribute; Pregnenolone; Preparation; Prevalence; Primary carcinoma of the liver cells; Property; Protein Binding; Publications; Receptor Activation; Reflex action; Scientist; Site; Small Business Innovation Research Grant; Solubility; Structure-Activity Relationship; Therapeutic Agents; Toxic effect; Vitamin E; Work; absorption; analog; aqueous; base; college; computational chemistry; design; drug candidate; drug development; drug standard; efficacy evaluation; improved; in vitro Assay; in vivo; in vivo Model; liver transplantation; meetings; mouse model; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; pre-clinical; pregnane X receptor; programs; public health relevance; scaffold; structural biology

 DESCRIPTION (provided by applicant): Non-Alcoholic Fatty Liver Disease (NAFLD) is a malady of increasing prevalence because of the growing population of individuals with obesity, metabolic syndrome and diabetes. This multifactorial disorder, due to both environmental and genetic factors, affects 30% of Americans with a prevalence of nearly 90% in obese individuals. NAFLD can lead to non-alcoholic steatohepatitis (NASH) with a prevalence of 25% in persons with obesity, and NASH in turn can lead to hepatocellular carcinoma, and cirrhosis. The pregnane X receptor (PXR) has emerged as a potential target for treatment of NAFLD as activation of this receptor results in hepatic steatosis in animal models. We have identified and characterized novel human pregnane X receptor antagonist FLB-12 that specifically disrupts the function of activated (agonist ligand-bound) PXR, but does not inhibit basal levels of PXR activity. This compound has shown to be a selective PXR antagonist in a variety of in vitro and in vivo models. More specifically and importantly FLB-12 was able to statistically improve an important disease component (hepatocyte ballooning) in a murine NAFLD model. However the potency and certain drug properties of FLB-12 need to be improved in order for this compound to be considered a viable predevelopment candidate. We will realize these goals by accomplishing the following specific aims: Aim 1: Identify structure-activity relationships (SAR) for allosteric antagonism of PXR to improve potency and ADME/PK properties. The goals of this aim are to increase PXR antagonist potency and selectivity as assessed by complementary in vitro assays already established in the Mani lab. Our objective is to reduce the IC50 values in each of these assays into the sub-micromolar range. Aim 2: Evaluate ADME/PK properties for PXR antagonists meeting criteria of Aim 1. We will explore potential drug properties by obtaining in vitro absorption, distribution, metabolism and excretion (ADME) data for up to 10 compounds. One or two of the most promising compounds will be evaluated for pharmacokinetic (PK) parameters in mice (IV administration) to determine in vivo terminal half-life, volume of distribution and clearance. These goals will be accomplished by combining the pharmaceutical and medicinal chemistry expertise of the scientists at the Fox Chase Chemical Diversity Center, Inc. (www.fc-cdci.com), the PXR structural biology expertise of Collaborations in Chemistry, and the extensive expertise of the Mani Lab at the Albert Einstein College of Medicine in the preclinical aspects of PXR modulators. Once we achieve the aims of this proposal, we will be well-positioned to transition into a lead optimization and full drug development program as part of the more extensive Phase II SBIR period of study where our goals would be to find preclinical drug candidates targeting PXR that we can evaluate in detailed NAFLD models under oral administration.

 描述（由申请人提供）：非酒精性脂肪性肝病（NAFLD）是一种由于肥胖、代谢综合征和糖尿病患者人数不断增加而患病率不断增加的疾病。这种多因素疾病，由于环境和遗传因素，影响了30%的美国人，在肥胖个体中的患病率接近90%。NAFLD可导致非酒精性脂肪性肝炎（NASH），在肥胖人群中的患病率为25%，而NASH又可导致肝细胞癌和肝硬化。胆固醇X受体（PXR）已经成为治疗NAFLD的潜在靶标，因为该受体的激活导致动物模型中的肝脂肪变性。我们已经鉴定并表征了新型人胆甾烷X受体拮抗剂FLB-12，其特异性地破坏活化的（激动剂配体结合的）PXR的功能，但不抑制基础水平的PXR活性。该化合物已在多种体外和体内模型中显示为选择性PXR拮抗剂。更具体且重要的是，FLB-12能够在统计学上改善鼠NAFLD模型中的重要疾病组分（肝细胞气球样变）。然而，FLB-12的效力和某些药物特性需要改进，以便将该化合物视为可行的预开发候选物。我们将通过实现以下具体目标来实现这些目标：目标1：确定PXR的变构拮抗作用的结构-活性关系（SAR），以提高效力和ADME/PK特性。这一目标的目的是增加PXR拮抗剂的效力和选择性，通过Mani实验室已经建立的补充体外试验进行评估。我们的目标是将这些测定中的每一个的IC 50值降低到亚微摩尔范围内。目的2：评价符合目的1标准的PXR拮抗剂的ADME/PK特性。我们将通过获得多达10种化合物的体外吸收、分布、代谢和排泄（ADME）数据来探索潜在的药物特性。将评价一种或两种最有希望的化合物在小鼠中的药代动力学（PK）参数（IV给药），以确定体内终末半衰期、分布容积和清除率。这些目标将通过结合福克斯大通化学多样性中心的科学家的制药和药物化学专业知识来实现。（www.fc-cdci.com）、化学合作组织的PXR结构生物学专业知识以及阿尔伯特·爱因斯坦医学院Mani实验室在PXR调节剂临床前方面的广泛专业知识。一旦我们实现了这一提议的目标，我们将处于有利地位，过渡到一个领先的优化和完整的药物开发计划，作为更广泛的II期SBIR研究的一部分，我们的目标是找到靶向PXR的临床前候选药物，我们可以在口服给药的详细NAFLD模型中进行评估。