Role of biotransformation studies in minimizing metabolism-related liabilities in drug discovery.
Metabolism-related liabilities continue to be a major cause of attrition for drug candidates in clinical development. Such problems may arise from the bioactivation of the parent compound to a reactive metabolite capable of modifying biological materials covalently or engaging in redox-cycling reactions leading to the formation of other toxicants. Alternatively, they may result from the formation of a major metabolite with systemic exposure and adverse pharmacological activity. To avert such problems, biotransformation studies are becoming increasingly important in guiding the refinement of a lead series during drug discovery and in characterizing lead candidates prior to clinical evaluation. This article provides an overview of the methods that are used to uncover metabolism-related liabilities in a pre-clinical setting and offers suggestions for reducing such liabilities via the modification of structural features that are used commonly in drug-like molecules.
Shu
Yue-Zhong
YZ
Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, USA. YueZhong.Shu@bms.com
Johnson
Benjamin M
BM
Yang
Tian J
TJ
D000818:Animals; D035843:Biomedical Research / Q000379:methods* / Q000639:trends; D001711:Biotransformation; D015195:Drug Design; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D013678:Technology, Pharmaceutical / Q000379:methods* / Q000639:trends
D004364:Pharmaceutical Preparations