Peripherally Selective CB1 Receptor Antagonists for Alcoholic Liver Disease

描述(由申请人提供)：以进行性肝病为特征的肝硬变是全球慢性酒精滥用导致发病率的主要原因。此外，肝纤维化还与肝细胞癌的发病率增加有关，肝细胞癌通常是致命的。目前还没有被批准的治疗酒精性肝纤维化的药物。内源性大麻素受体(CBR)，特别是CB1R，最近已成为治疗肝纤维化和其他相关疾病的预临床验证靶点。CB1R和CB2R均在中枢神经系统(CNS)表达。它们也存在于外周的各种组织中，包括肝脏。CB1R和CB2R在肝病的发生发展中起着相互作用。虽然CB1R和CB2R在正常肝脏中有少量表达，但在肝损伤或酒精性肝病发生时，它们在肝细胞和肝星状细胞(HSC)中显著上调。过去的研究也表明，CB1R的拮抗剂是进一步开发和试验治疗酒精性肝病的有前途的候选药物。目前可用的CB1R拮抗剂不适合用于治疗肝纤维化，因为它们对中枢神经系统有有害影响。例如，选择性CB1R拮抗剂SR141716(Rimonabant(C))由赛诺菲-安万特开发，用于治疗肥胖，在患者中产生与中枢神经系统相关的不良副作用，包括抑郁和自杀念头。在大量患有抑郁症的酗酒者中，这是一个特别令人担忧的问题。这些副作用导致FDA拒绝该化合物在美国使用，并在批准后从欧洲撤回。尽管有这些限制，RIO试验和后续研究的数据表明，撇开中枢系统相关效应不谈，SR141716总体上耐受性良好，并具有几个积极的非中枢系统相关特性，如改善血脂状况和使用者的胰岛素敏感性。这些结果还表明，在酒精性肝病和其他相关病因中靶向CB1R的有效策略是开发不能渗透血脑屏障(BBB)的外周限制性CB1R拮抗剂，这是本研究项目的总体目标。通过我们正在进行的NIAAA资助的小额研究资助(R03AA017514)，我们已经确定了基于核心SR141716结构的CB1R拮抗剂，这些拮抗剂降低了BBB的渗透性。使用这些在CB1R具有药理相关活性的早期化合物作为模板，通过合理的药物设计进一步精炼，我们希望开发和测试下一代化合物，作为通过以下特定目标治疗酒精性肝纤维化的药物开发的先导：通过目标1，我们建议合成更多具有结构特性的SR141716类似物，旨在限制它们在血脑屏障中的转运。通过目标2，我们建议使用体外功能分析来表征这些合成的化合物。此外，我们还将研究选定数量的活性化合物在啮齿动物体内的药代动力学特性，包括血脑屏障通透性和半衰期。此外，我们建议进行基因表达谱实验，以比较和对比我们最好的Lead对稳定表达CB1R的肝星状细胞系SR141716的全基因组影响。通过目标3，我们建议对我们最好的化合物进行体内酒精脂肪变性的Lieber-DeCarli啮齿动物模型的有效性测试。我们将评估ALD的几个生物标记物，以监测测试化合物在这个公认的酒精性肝病模型中的有效性。 公共卫生相关性：项目叙述酒精性肝病具有很高的死亡率，并增加了发生肝癌的机会。目前还没有FDA批准的药物来治疗这种疾病。我们的目标是开发治疗酒精性肝病的药物，方法是针对一种名为1型大麻素受体的特定蛋白质，这种蛋白质已被认为是这种疾病的靶点。利用药物化学和药理学，我们建议合成和测试抑制1型大麻素受体功能的化合物。

DESCRIPTION (provided by applicant): Cirrhosis characterized by progressive liver disease is a leading cause of morbidity from chronic abuse of ethanol worldwide. In addition, hepatic fibrosis is also associated with increased rates of hepatocellular carcinoma, which is usually fatal. There is currently no approved drug to treat alcoholic liver fibrosis. The endocannabinoid receptors (CBRs), particularly CB1R, have recently emerged as pre-clinically validated targets to treat liver fibrosis and other related disorders. Both CB1R and CB2R are expressed in the central nervous system (CNS). They also exist peripherally in a variety of tissues including the liver. CB1R and CB2R play reciprocal roles in progression of liver disease. While CB1R and CB2R are marginally expressed in normal liver, they undergo marked upregulation upon liver injury or onset of alcoholic liver disease in hepatocytes and hepatic stellate cells (HSC). Past studies also indicate that antagonists of CB1R are promising candidates for further development and testing to treat alcoholic liver disease. Currently available CB1R antagonists are unsuitable for use in liver fibrosis due to their deleterious effects on the CNS. For example, the selective CB1R antagonist SR141716 (Rimonabant(c)), which was developed by Sanofi-Aventis for obesity, produced undesirable CNS-related side effects in patients including depression and suicidal ideation. This is a particular concern in a large population of alcoholics who suffer from depression. These side effects led the FDA to reject this compound for use in the US and it was withdrawn from Europe post-approval. In spite of these limitations, data from the Rimonabant for Obesity (RIO) trial and follow-up studies indicate that CNS related effects aside, SR141716 is well tolerated in general and has several positive non-CNS related properties, such as improved blood lipid profile, and insulin sensitivity in users. These results also indicate that an effective strategy to target CB1R in alcoholic liver disease and other related etiologies that would by-pass the CNS-related concerns of chronically antagonizing this receptor is to develop peripherally restricted CB1R antagonists that cannot permeate the blood-brain barrier (BBB), which is the overall goal of this research project. Through our ongoing NIAAA-funded small research grant (R03AA017514), we have identified CB1R antagonists based upon the core SR141716 structure that have reduced permeability across the BBB. Using these early compounds with pharmacologically relevant activity at CB1R as templates for further refinement through rational drug design, we expect to develop and test the next generation of compounds to serve as leads for medications development to treat alcoholic liver fibrosis through the following specific aims: Through aim 1 we propose to synthesize additional analogs of SR141716 with structural properties designed to limit their transport across the BBB. Through aim 2, we propose to characterize these synthesized compounds using functional in vitro assays. Further, we will also study pharmacokinetic properties of a select number of active compounds in rodents including BBB permeability and half-life. Additionally, we propose to conduct gene expression profiling experiments to compare and contrast the genome-wide effects of our best lead to SR141716 in a hepatic stellate cell-line stably expressing CB1R. Through aim 3, we propose to conduct efficacy testing of our best compound in an in vivo Lieber-DeCarli rodent model of alcoholic steatosis. We will evaluate several biomarkers of ALD to monitor efficacy of the test compound in this well-established model of alcoholic liver disease. PUBLIC HEALTH RELEVANCE: Project Narrative Alcoholic liver disease has a high mortality rate and increases the chance of developing liver cancer. There are no FDA-approved drugs available currently to treat this disease. Our goal is to develop drugs to treat alcoholic liver disease by targeting a particular type of protein called the type 1 cannabinoid receptor that has been implicated as a target for this disorder. Using medicinal chemistry and pharmacology, we propose to synthesize and test compounds that inhibit the function of type 1 cannabinoid receptors.