Woods Jack, Snape Mike, Smith Mark A
Department of Experimental Psychology, South Parks Road, Oxford OX1 3UD, UK.
Biochim Biophys Acta. 2007 Apr;1772(4):503-8. doi: 10.1016/j.bbadis.2006.12.004. Epub 2006 Dec 13.
The cell cycle of hypothesis of neural dysfunction in chronic neurodegenerative conditions such as Alzheimer's disease (AD) offers a unified approach to understanding both existing and novel strategies for drug development. At the present time, a ligand based approach is a pragmatic solution for identifying new chemical leads on which to base future discovery and optimisation. We have pursued a ligand based approach on the basis of public domain data to identify existing compounds capable of abrogating the cell cycle at the G0-G1 interface. Selected on this basis, irrespective of the tissue under study, we identified several classes of compounds as potential chemical leads. Of these compounds, at least ten have already been shown to be neuroprotective in animal models of acute neurodegeneration. Such compounds could form the basis of a screening exercise after development of suitable screening tools. Progressing of chemical leads through such an approach will be more efficient if future leads display relevant "drug-like" properties. Further, drug development in this arena should take account of the special concerns raised by targeting an elderly population. This will involve accounting for frequent polypharmacy in the aging population, and age-related alterations in physiology.
在诸如阿尔茨海默病（AD）等慢性神经退行性疾病中，神经功能障碍的细胞周期假说为理解现有和新型药物开发策略提供了一种统一的方法。目前，基于配体的方法是一种务实的解决方案，用于识别新的化学先导物，作为未来发现和优化的基础。我们基于公共领域数据采用了基于配体的方法，以识别能够在G0-G1界面阻断细胞周期的现有化合物。在此基础上进行选择，无论所研究的组织如何，我们确定了几类化合物作为潜在的化学先导物。在这些化合物中，至少有十种已在急性神经退行性疾病的动物模型中显示出神经保护作用。在开发合适的筛选工具后，此类化合物可构成筛选工作的基础。如果未来的先导物具有相关的“类药物”特性，通过这种方法推进化学先导物的研发将更有效。此外，该领域的药物开发应考虑到针对老年人群体所引发的特殊问题。这将涉及考虑老年人群体中频繁的多重用药情况以及与年龄相关的生理变化。
