化学
代谢物分析
计算生物学
药品
药物发现
代谢物
代谢组学
仿形(计算机编程)
药理学
药物开发
小分子
药物代谢
生物信息学
代谢组
作者
Matthew A. Cerny,Amit S. Kalgutkar,R. Scott Obach,Raman Sharma,Douglas K. Spracklin,Gregory S. Walker
标识
DOI:10.1021/acs.jmedchem.9b01840
摘要
At one time, biotransformation was a descriptive activity in pharmaceutical development, viewed simply as structural elucidation of drug metabolites, completed only once compounds entered clinical development. Herein, we present our strategic approach using structural elucidation to enable chemistry design/SAR development. The approach considers four questions that often present themselves to medicinal chemists optimizing their compounds for candidate selection: (1) What are the important clearance mechanisms that mediate the disposition of my molecule? (2) Can metabolic liabilities be modulated in a favorable way? (3) Does my compound undergo bioactivation to a reactive metabolite? (4) Do any of the metabolites possess activity, either on- or off-target? An additional question necessary to support compound development relates to metabolites in safety testing (MIST) and our approach also addresses this question. The value in structural elucidation is derived from its application to better design molecules, guide their clinical development, and underwrite patient safety.
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