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

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• 作者：Arup K. Ghose ; Torsten Herbertz ; Robert L. Hudkins ; Bruce D. Dorsey ; John P. Mallamo
• 刊名：ACS Chemical Neuroscience
• 出版年：2012
• 出版时间：January 18, 2012
• 年：2012
• 卷：3
• 期：1
• 页码：50-68
• 全文大小：720K
• 年卷期：v.3,no.1(January 18, 2012)
• ISSN：1948-7193

文摘

The central nervous system (CNS) is the major area that is affected by aging. Alzheimer鈥檚 disease (AD), Parkinson鈥檚 disease (PD), brain cancer, and stroke are the CNS diseases that will cost trillions of dollars for their treatment. Achievement of appropriate blood鈥揵rain 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 <76 脜² (25鈥?0 脜²), (ii) at least one (one or two, including one aliphatic amine) nitrogen, (iii) fewer than seven (two to four) linear chains outside of rings, (iv) fewer than three (zero or one) polar hydrogen atoms, (v) volume of 740鈥?70 脜³, (vi) solvent accessible surface area of 460鈥?80 脜², and (vii) positive QikProp parameter CNS. The ranges within parentheses may be used during lead optimization. One violation to this proposed profile may be acceptable. The chemoinformatics approaches for graphically analyzing multiple properties efficiently are presented.

Keywords:

Central nervous system; CNS; CNS drugs; non-CNS drugs; polar surface area; aliphatic amine; linear chains; polar hydrogen; molecular volume; solvent accessible surface area; chemical substructures; physicochemical property profile; chemoinformatics