Development of Estrogen Receptor B Selective Receptor Agonists to Treat Neuropath

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。它对标准的镇痛疗法是难治性的，目前所有的神经性疼痛药物对大约30%的患者提供缓解。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和日益严重的疾病，显然存在未满足的医疗需求。阿卡迪亚制药公司发现了高选择性雌激素受体β （ER¿）激动剂，对神经性疼痛的动物模型非常有效。由于它们对雌激素受体的高选择性，它们不会产生由于雌激素受体α (ERa)激活而导致的女性化副作用，并且显示出候选药物的许多理想属性：没有明显的心血管危险或致突变性风险，很少或没有药物相互作用的可能性。大鼠接受10倍于最大有效剂量的剂量时，未见明显的副作用。这些化合物在人体肝脏中具有良好的代谢稳定性，提示人体口服给药是可行的。此外，当这些化合物舌下给药时，它们在大鼠中的生物利用度很高（约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。在这项U44转化研究资助中，我们将开发雌激素受体激动剂作为治疗神经性疼痛的临床候选药物。在第一阶段，我们将率先确定它们在肝细胞中的代谢谱、体内PK特性以及它们在口腔、表皮和肠道（Caco2）细胞中的通透性。代谢和PK研究将使我们能够预测人类的生物利用度和口服给药的可行性，而渗透性研究将提供口腔/舌下和透皮给药的可行性数据。在进行PK研究的同时，我们还将完成遗传、心血管或药物-药物相互作用的体外安全性筛选。我们将采用具有最佳整体特征的化合物，并在启动符合fda要求的GLP 2期SBIR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。我们的目标是确定一种ER受体激动剂，可以口服、舌下或经皮给药，并且具有可控的毒性，或者理想情况下没有毒性，包括血浆浓度至少比药理学有效浓度高10倍的NOEL。在第二阶段，先导化合物将接受IND毒理学、心血管和遗传毒理学研究，为IND申请提供必要的支持数据。这些研究将需要gmp级材料，并将包括体外和体内遗传毒性研究（Ames试验、染色体畸变试验、大鼠微核）、心血管毒性研究（hERG通道抑制、有意识的心血管监测、遥测狗或猴子），以及在啮齿动物和非啮齿动物模型中进行为期28天的重复剂量毒性研究。然后，我们将与FDA安排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。

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.