Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery

The central nervous system (CNS) is the major area that
is affected
by aging. Alzheimer’s disease (AD), Parkinson’s disease
(PD), brain cancer, and stroke are the CNS diseases that will cost
trillions of dollars for their treatment. Achievement of appropriate
blood–brain barrier (BBB) penetration is often considered a
significant hurdle in the CNS drug discovery process. On the other
hand, BBB penetration may be a liability for many of the non-CNS drug
targets, and a clear understanding of the physicochemical and structural
differences between CNS and non-CNS drugs may assist both research
areas. Because of the numerous and challenging issues in CNS drug
discovery and the low success rates, pharmaceutical companies are
beginning to deprioritize their drug discovery efforts in the CNS
arena. Prompted by these challenges and to aid in the design of high-quality,
efficacious CNS compounds, we analyzed the physicochemical property
and the chemical structural profiles of 317 CNS and 626 non-CNS oral
drugs. The conclusions derived provide an ideal property profile for
lead selection and the property modification strategy during the lead
optimization process. A list of substructural units that may be useful
for CNS drug design was also provided here. A classification tree
was also developed to differentiate between CNS drugs and non-CNS
oral drugs. The combined analysis provided the following guidelines
for designing high-quality CNS drugs: (i) topological molecular polar
surface area of

中枢神经系统（CNS）是受衰老影响的主要区域。阿尔茨海默病（AD）、帕金森病（PD）、脑癌和中风等中枢神经系统疾病的治疗将耗费数十亿美元。在CNS药物发现过程中，实现适当的血脑屏障（BBB）渗透率常常被视为一个重大的障碍。另一方面，BBB渗透率对于许多非CNS药物靶点来说可能是一种不利因素，而对中枢神经系统药物与非中枢神经系统药物在物理化学和结构上的差异进行清晰的理解，可能有助于两个研究领域的进展。鉴于中枢神经系统药物发现中存在的众多挑战以及成功率较低，制药公司开始降低其对中枢神经系统药物发现工作的优先级。受这些挑战的启发，为了辅助设计高质量、有效性的中枢神经系统化合物，我们分析了317种中枢神经系统药物和626种非中枢神经系统口服药物的物理化学性质和化学结构特征。得出的结论为原药选择和原药优化过程中的性质改良策略提供了理想的性质轮廓。此外，还提供了一份可能对中枢神经系统药物设计有用的亚结构单元列表。同时，还开发了一个分类树，用于区分中枢神经系统药物和非中枢神经系统口服药物。综合分析为设计高质量中枢神经系统药物提供了以下指导原则：（i）拓扑分子极性表面积（TPSA）应...