Efficacy of a Novel Neuroprotective Compound in Nonhuman Primate

描述（由申请人提供）：由于神经精神疾病的治疗方案严重缺乏，迫切需要促进将基础神经科学的发现转化为患者的新治疗方法。通过活体小鼠体内筛选，鉴定出一种具有生物活性的氨基丙基咔唑，命名为P7C3，具有强效的前神经源性和神经保护特性。对这种化学支架进行了多年的结构-活性关系研究，优化了效力和功效，同时最大限度地减少了药物开发的实际和感知负担。P7C3类分子稳定线粒体膜电位，保护神经元免于细胞死亡。P7C3及其更有效的变体，P7C3A20，具有显著的保护作用，现已在动物衰老模型，阿尔茨海默病，帕金森氏病和肌萎缩侧索硬化症中得到证实。一个新的挑战是提供额外的证据，证明这些化合物可能对人类大脑有益。应对这一挑战的第一步是证明这些最有效的化合物（P7C3A20）在非人灵长类动物大脑中具有前神经形成和/或保护作用。人类脑部疾病是由复杂的人类行为（即认知、情感等）的变化来定义的，对神经保护化合物的治疗效果的评估可能最终受益于对动物物种的研究，这些动物物种与人类的关系比小鼠更密切。此外，文献中充满了对小鼠有效但对人类无效的药物的例子。恒河猴（Macaca mulatta）在人类身上提供了一个有用的代理，因为它们展示了人类生理、解剖和行为的许多特征。因此，恒河猴是研究各种复杂的人类大脑疾病的理想对象。然而，在我们开始探索P7C3类分子在复杂的非人类灵长类动物疾病模型中的治疗潜力之前，我们必须首先确定P7C3类分子在灵长类动物大脑中的神经保护作用。在这里，我们提出了非人类灵长类动物海马神经发生作为暴露于P7C3A20的功能的量化，以便提供一种快速，成本有效和直接的方法来评估恒河猴的神经保护效果。在非人类灵长类动物身上的临床前原理证明，可以为患有神经精神和神经退行性疾病（包括海马神经发生减少和/或更广泛的神经变性）的患者提供一个将基础科学转化为新的治疗方法的机会。

DESCRIPTION (provided by applicant): Due to a profound lack of treatment options for neuropsychiatric disease, there is a critical need to facilitate the translation of findings from basic neuroscience to new treatments for patients. Through an in vivo screen conducted in living mice, a biologically active aminopropyl carbazole, designated P7C3, was identified with potent proneurogenic and neuroprotective properties. A multi-year structure-activity-relationship study on this chemical scaffold has enabled optimization of potency and efficacy, while minimizing real and perceived liabilities for drug development. The P7C3 class of molecules stabilizes mitochondrial membrane potential and protects neurons from cell death. Significant protective efficacy of P7C3 and it's more potent and efficacious variant, P7C3A20, has now been demonstrated in animal models of aging, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. A new challenge is to provide additional evidence that these compounds could be beneficial to the human brain. An initial step to meet this challenge is to demonstrate that the most effective of these compounds (P7C3A20) has a proneurogenic and/or protective effect in the nonhuman primate brain. Human brain disorders are defined by changes in complex human behaviors (i.e., cognition, emotion etc.), and evaluation of the therapeutic effects of neuroprotective compounds may ultimately benefit from studies in animal species that are more closely related to humans than are mice. Moreover, the literature is replete with examples of drugs that work well in mice but are not therapeutically beneficial in humans. Rhesus macaques (Macaca mulatta) provide a useful proxy for efficacy in the human, as they demonstrate many features of human physiology, anatomy and behavior. Rhesus monkeys are thus ideal for studying a variety of complex human brain disorders. However, before we can begin to explore the therapeutic potential of the P7C3 class of molecules in sophisticated nonhuman primate diseases models, we must first establish a neuroprotective role for the P7C3 class of molecules in the primate brain. Here, we propose quantification of nonhuman primate hippocampal neurogenesis as a function of exposure to P7C3A20, in order to provide a rapid, cost effective and straightforward means of assessing efficacy of neuroprotection in the rhesus monkey. Preclinical proof of principle in a nonhuman primate could provide an opportunity to translate basic science into a new therapeutic approach for patients suffering from both neuropsychiatric and neurodegenerative diseases involving diminished hippocampal neurogenesis and/or broader neurodegeneration.