Metabolic stability screening strategies

Advances in techniques for chemical synthesis allow medicinal chemists to synthesize hundreds to thousands of compounds per month. Metabolic stability screening in liver microsomes is used extensively in early discovery to select the analogs or compounds most likely to have favorable pharmacokinetic parameters. This provides information on the relation of structure to stability, thus guiding synthesis strategies. 

Figure 6.2. Strategies for the design of decision trees for new compound evaluation. ADME-based screens can be incorporated in many places in a decision tree, three examples are illustrated A, ADME screens are run as a panel in parallel with early activity screens, compounds proceed to further biological screens after meeting set criteria B, ADME screens are run after a compound meets set potency criteria and compounds proceed to further biological screens after meeting set ADME criteria C, critical ADME screen (metabolic stability in this case) is run on compounds that meet potency criteria and then full ADME screen panel is run before compounds proceed.

Zhao SX, Forman D, Wallace N, Smith BJ, Meyer D, Kazolias D, Gao F, Soglia J, Cole M, Nettleton D.Simple strategies for reducing sample loads in in vitro metabolic stability high-throughput screening experiments a comparison between traditional, two-time-point and pooled sample analyses. J Pharm Sci 2005 94 38-45. 

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