Small molecule inhibitor of amyloid precursor protein synthesis

描述(由申请人提供)：该SBIR将产生的产品是一种治疗阿尔茨海默病(AD)的小分子药物疗法，其工作原理是抑制淀粉样前体蛋白的合成。AD占所有痴呆症的三分之二，全球有2600多万人患有AD，美国有400多万人患有AD。阿尔茨海默病的淀粉样假说认为，大脑中淀粉样β蛋白(Ab)水平的增加，可能以聚集的形式，介导了一系列导致神经元功能障碍、变性和临床痴呆的事件。目前，目前批准的治疗方法主要被认为是有症状的。尽管目前有大量潜在的改善疾病的治疗策略正在开发中，主要集中在淀粉样斑块和NFT的主要成分Ab和tau上，但还没有一种方法被批准用于AD的治疗。[+]-苯丝氨酸-酒石酸盐是一种实验药物，已获得QR Pharma独家许可。在细胞培养和动物体内，[+]-苯丝氨酸-酒石酸盐都被发现可以降低淀粉样前体蛋白的合成速度。APP mRNA被有效地翻译，并可以在其5‘-非翻译区(5’-UTR)的水平上进行调节。[+]-苯丝氨酸-酒石酸盐通过这种5‘-UTR降低APP的合成速率，在神经元培养和小鼠两次ip后，APP蛋白和抗体(1-40和1-42)减少了高达50%。和口服给药。[+]-通过FDA要求的临床前研究，已成功开发出苯丝氨酸-酒石酸盐，已获FDA批准用于人类使用，并已开始第一阶段临床试验(单次和重复剂量)。[+]-苯丝氨酸-酒石酸盐在口服后的临床前毒理学研究中在啮齿动物和狗中都有很好的耐受性，同样，在健康的老年志愿者中也有很好的耐受性。将人类在耐受性良好的剂量后达到的血浆浓度与降低抗体浓度的啮齿类动物的血浆浓度进行比较，表明可以在人类身上达到有效浓度。总而言之，这些数据表明[+]-苯丝氨酸-酒石酸盐是一种口服生物可用小药物，很容易进入大脑，可以有效地降低抗体，而不会产生毒性。在所有物种中，血浆Posiphen在口服给药后半衰期为2-4小时消失，通过其[+]-N1-和[+]-N8-降冰片酚中间体产生主要代谢物[+]-N1，N8-双降冰片酚。这些中间体已被发现具有抗胆碱酯酶活性，由于它们的浓度比母药高得多，因此需要对其进行表征和优化，以支持在AD受试者下一阶段的临床研究中继续评估活性。 与公共健康相关：这种SBIR将产生的产品是一种治疗阿尔茨海默病的小分子药物疗法，它通过抑制疾病的分子原因发挥作用。阿尔茨海默氏症占所有痴呆症的三分之二。尽管目前正在开发一些可能改变疾病的治疗策略，但到目前为止还没有一种得到批准。

DESCRIPTION (provided by applicant): The product that will result from this SBIR is a small molecule drug therapy for Alzheimer's Disease (AD) that works by inhibiting amyloid precursor protein synthesis. AD accounts for two-thirds of all dementia, afflicting more than 26 million people worldwide, and in excess of 4 million Americans. The amyloid hypothesis of AD proposes that increased levels of amyloid-beta (Ab) peptides in the brain, possibly in their aggregated form, mediate a cascade of events leading to neuronal dysfunction, degeneration and clinical dementia. At present, currently approved therapies are considered to be primarily symptomatic. Although a large number of potentially disease-modifying therapeutic strategies are in current development, primarily focused on Ab and tau, the primary constituents of amyloid plaques and NFTs, respectively, none has been approved for AD treatment. [+]-Phenserine-tartrate is an experimental drug that has been exclusively licensed by QR Pharma. In both cell cultures and in animals [+]-phenserine-tartrate has been found to lower the rate of amyloid precursor protein synthesis. APP mRNA is efficiently translated and can be regulated at the level of its 5'-untranslated region (5'-UTR). [+]-phenserine-tartrate acts to lower the rate of APP synthesis via this 5'-UTR, reducing APP protein as well as Ab (1-40 and 1-42) by up to 50% in neuronal cultures and mice following both i.p. and oral administration. [+]-Phenserine-tartrate has been successfully developed through FDA required preclinical studies, has been FDA-approved for human use, and has begun Phase 1 clinical trials (single and repeated dosing). [+]- Phenserine-tartrate was well tolerated in both rodents and dogs in preclinical toxicological studies following oral administration and, likewise, was well tolerated in healthy elderly volunteers after oral dosing. A comparison of plasma concentrations achieved in humans following a well-tolerated dose with Ab-lowering concentrations in rodents suggests that effective concentrations can be achieved in humans. Collectively, these data indicate that [+]-phenserine-tartrate is an orally bioavailable small drug that readily enters the brain and can effectively lower Ab without toxicity. In all species, plasma Posiphen disappeared with a half-life of 2 to 4 hours following oral dosing, generating the major metabolite, [+]-N1,N8-bisnorposiphen, via its [+]-N1- and [+]-N8-norposiphen intermediates. These intermediates have been found to possess anticholinesterase activity, and since they achieve substantially greater concentrations than the parent drug, require to be characterized and optimized to support continued assessment of activities in the next phase of clinical studies in AD subjects. PUBLIC HEALTH RELEVANCE: The product that will result from this SBIR is a small molecule drug therapy for Alzheimer's Disease that works by inhibiting a molecular cause of the disease. Alzheimer's Disease accounts for two-thirds of all dementia. Although a number of potentially disease-modifying therapeutic strategies are in current development, none has so far been approved.