Development of Estrogen Receptor B Selective Receptor Agonists to Treat Neuropath

开发雌激素受体 B 选择性受体激动剂来治疗神经病

• 批准号: 8264182
• 负责人: ETHAN Samuel BURSTEIN
• 金额: $ 30万
• 依托单位: ACADIA PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8264182
• 关键词: Address; Adverse effects; Affect; Agonist; Ames Assay; Analgesics; Animal Model; Biological Assay; Biological Availability; Canis familiaris; Cardiovascular system; Cells; Characteristics; Chromosome abnormality; Chronic; Chung model; Clinical; Conscious; Data; Dependency; Development; Disease; Dose; Drug Delivery Systems; Drug Interactions; Drug Kinetics; Drug Packaging; Estrogen Receptor 1; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Genetic; Genetic Screening; Goals; Grant; Hepatocyte; Human; Hyperalgesia; In Vitro; Inflammation; Intestines; Investigational Drugs; Lead; Liquid substance; Liver; Lung; Maximum Tolerated Dose; Medical; Metabolic; Metabolism; Methods; Micronucleus Tests; Modeling; Monitor; Monkeys; Motor Activity; Non-Rodent Model; Oral; Pathway interactions; Patients; Pb clearance; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma; Preclinical Testing; Property; Rattus; Refractory; Regimen; Research Project Grants; Risk; Rodent; Rodent Model; Safety; Schedule; Sedation procedure; Small Business Innovation Research Grant; Specificity; Stomach; Testing; Therapeutic; Toxic effect; Toxicogenetics; Toxicology; Translational Research; United States; animal efficacy; control trial; drug candidate; efficacy testing; genotoxicity; human subject; in vivo; meetings; micronucleus; nervous system disorder; novel; painful neuropathy; programs; public health relevance; receptor; safety study; safety testing; telemetering

DESCRIPTION (provided by applicant): Neuropathic pain is a serious neurological disorder affecting approximately 1.8 million people in the United States. It is refractory to standard analgesic therapies, with all current neuropathic pain drugs providing relief to approximately 30% of patients. In addition, these drugs all have significant side effects. Consequently there is a clear unmet medical need for new safe and effective drugs to treat this serious and growing disorder. Acadia Pharmaceuticals has discovered highly selective estrogen receptor beta (ER¿)-agonists that are highly efficacious in animal models of neuropathic pain. Because of their high selectivity for ER¿, they do not produce the feminizing side effects attributed to estrogen receptor alpha (ERa) activation and display many desirable attributes for a drug candidate: no apparent cardiovascular liability or mutagenicity risks, and little or no potential for drug-drug interactions. No apparent side effects were seen in rats receiving doses 10x above maximally effective doses. These compounds have good metabolic stability in human liver, suggesting oral dosing in humans is feasible. Further, their bioavailability in rats is high (>70%) when the compounds are given sublingually. Thus we believe we have several opportunities to develop these compounds as analgesic drugs. In this U44 Translational Research grant we will develop ER¿ agonists as clinical candidates for treating neuropathic pain. In Phase 1, we will take leads, and determine their metabolic profiles in hepatocytes, their in vivo PK characteristics, and their permeability properties across buccal, epidermal, and intestinal (Caco2) cells. The metabolism and PK studies will allow us to predict the bioavailability in humans, and feasibility of oral dosing, while the permeability studies will provide data on the feasibility of buccal/sublingual and transdermal dosing. We will also complete in vitro safety screens for genetic, cardiovascular, or drug-drug interaction liabilities in parallel to the PK studies. We will take the compound with the best overall profile and conduct preliminary in vivo rodent toxicology and cardiovascular safety studies before initiating FDA-compliant GLP studies in Phase 2 SBIR studies. Our goal is to identify 1 ER¿ agonist that can be administered to humans orally, sublingually or transdermally and that has manageable, or ideally no toxicity, including a NOEL at plasma concentrations at least 10-fold above pharmacologically effective concentrations. In Phase 2, the lead compound will be subject to IND-enabling toxicology, cardiovascular and genetic toxicology studies to provide the necessary supporting data for an IND submission. These studies will require GMP-grade material and will include in vitro and in vivo studies for genetic toxicity (Ames assay, chromosomal aberration assay, rat micronucleus), cardiovascular toxicity (hERG channel inhibition, cardiovascular monitoring in conscious, telemetered dogs or monkeys) and repeat dose toxicity studies for 28 days in rodent and non-rodent models. We will then schedule a pre-IND meeting with FDA to discuss the overall development pathway and understand key regulatory issues that may need to be addressed during the clinical program. PUBLIC HEALTH RELEVANCE: Acadia Pharmaceuticals is devoted to the development of novel, safe and efficacious drugs to treat neurological disorders and in this grant we propose to develop drugs targeting estrogen receptor B (ER¿) to treat neuropathic pain, a serious neurological disorder that is generally not treated effectively by available medications. We have identified highly selective ER¿ selective agonists and have conducted extensive preclinical testing with these prototypical drugs and found they were highly effective in a number of animal models of neuropathic pain and they had many desirable pharmaceutical properties with no apparent side effects in rodents. Our goal in this grant is to optimize our ER¿ agonists and conduct standard IND enabling studies including toxicology to be able to begin clinical development of our ER¿ selective agonists for treating neuropathic pain.

描述（由申请人提供）：神经性疼痛是一种严重的神经系统疾病，影响美国约180万人。标准镇痛疗法难以治疗，目前所有神经性疼痛药物可缓解约30%的患者。此外，这些药物都有明显的副作用。因此，对于新的安全有效的药物来治疗这种严重的和日益增长的疾病，存在明显的未满足的医疗需求。 西印度群岛制药公司已经发现了高度选择性的雌激素受体β（ER）激动剂，在神经性疼痛的动物模型中非常有效。由于它们对ER α的高度选择性，它们不会产生归因于雌激素受体α（ER α）激活的女性化副作用，并显示出候选药物的许多理想属性：没有明显的心血管倾向或致突变风险，很少或没有药物相互作用的可能性。在接受高于最大有效剂量10倍剂量的大鼠中未观察到明显的副作用。这些化合物在人体肝脏中具有良好的代谢稳定性，表明人体口服给药是可行的。此外，当舌下给予化合物时，它们在大鼠中的生物利用度高（>70%）。因此，我们相信我们有几个机会开发这些化合物作为镇痛药物。 在U44转化研究资助中，我们将开发ER？激动剂作为治疗神经性疼痛的临床候选药物。在第1阶段，我们将采取线索，并确定其在肝细胞中的代谢特征，其体内PK特征，以及其在颊，表皮和肠（Caco 2）细胞中的渗透性。代谢和PK研究将使我们能够预测人体生物利用度和口服给药的可行性，而渗透性研究将提供关于口腔/舌下和透皮给药可行性的数据。我们还将在PK研究的同时完成遗传、心血管或药物相互作用的体外安全性筛选。我们将采用具有最佳总体特征的化合物，并在2期SBIR研究中启动FDA合规GLP研究之前进行初步的体内啮齿动物毒理学和心血管安全性研究。我们的目标是鉴定1种ER？激动剂，其可经口、舌下或经皮给予人类，并且具有可控制的或理想地无毒性，包括在血浆浓度至少高于有效浓度10倍时的诺埃尔。 在第2阶段，先导化合物将接受IND使能毒理学、心血管和遗传毒理学研究，为IND提交提供必要的支持数据。这些研究将需要GMP级材料，并将包括遗传毒性（艾姆斯试验、染色体畸变试验、大鼠微核）、心血管毒性（hERG通道抑制、清醒遥测犬或猴的心血管监测）的体外和体内研究以及啮齿动物和非啮齿动物模型中持续28天的重复给药毒性研究。然后，我们将与FDA安排一次IND前会议，讨论整体开发途径，并了解临床项目期间可能需要解决的关键监管问题。 公共卫生关系：Rendia制药公司致力于开发新型，安全和有效的药物来治疗神经系统疾病，在这项资助中，我们建议开发靶向雌激素受体B（ER）的药物来治疗神经性疼痛，这是一种严重的神经系统疾病，通常无法通过现有药物有效治疗。我们已经确定了高选择性ER选择性激动剂，并对这些原型药物进行了广泛的临床前试验，发现它们在许多神经性疼痛的动物模型中非常有效，并且它们具有许多理想的药物特性，在啮齿动物中没有明显的副作用。我们的目标是优化我们的雌激素受体激动剂，并进行标准的IND研究，包括毒理学研究，以便能够开始临床开发我们的雌激素受体选择性激动剂治疗神经性疼痛。