Efficacy of a Novel Neuroprotective Compound in Nonhuman Primate

描述(由申请人提供)：由于严重缺乏神经精神疾病的治疗选择，迫切需要促进将基础神经科学的研究成果转化为患者的新疗法。通过在活体小鼠身上进行的体内筛选，确认了一种具有生物活性的氨基丙基咔唑，命名为P7C3，具有强大的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，使效力和疗效得到优化，同时将药物开发的实际和预期风险降至最低。P7C3类分子稳定线粒体膜电位，保护神经元免受细胞死亡。P7C3及其更有效的变体P7C3A20具有显著的保护作用，现已在衰老、阿尔茨海默病、帕金森病和肌萎缩侧索硬化症的动物模型中得到证明。一个新的挑战是提供更多的证据，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化合物中最有效的(P7C3A20)在非人类灵长类动物的大脑中具有神经原和/或保护作用。人类大脑疾病的定义是复杂的人类行为(即认知、情感等)的变化，对神经保护化合物治疗效果的评估最终可能受益于对与人类关系比老鼠更密切的动物物种的研究。此外，文献中充斥着在老鼠身上起作用但对人类没有治疗益处的药物的例子。恒河猴(Macaca Mulatta)是一种有用的人体药效指标，因为它们显示了人类生理、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动物。然而，在我们开始探索P7C3类分子在复杂的非人类灵长类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，我们建议量化非人类灵长类动物海马区神经发生作为暴露于P7C3A20的函数，以便提供一种快速、经济有效和直接的方法来评估恒河猴神经保护的有效性。对非人类灵长类动物的临床前原则证明可能为患有神经精神疾病和神经退行性疾病的患者提供机会，将基础科学转化为新的治疗方法，这些疾病包括海马神经发生减少和/或更广泛的神经退行性变。

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.