Chapter 29 - Metabolic Stability Methods

Abstract

Metabolic stability is one of the most important properties in drug discovery. Stability often is a major liability for a lead series and needs improvement. Quantitative metabolic stability data are used to assess the extent of metabolic conversion, prioritize compounds for in vivo studies, and set priorities for discovery activities. Qualitative metabolite structure information indicates the sites of metabolic instability (“hot spots”) that medicinal chemists use to plan structural modifications for improved stability. Metabolic stability data are useful for prospectively selecting compounds for in vivo dosing studies and for retrospectively diagnosing the causes of poor pharmacokinetic (PK) performance or lack of in vivo activity. Metabolic stability assays incubate the test compound with a selected metabolic stability material. Detection methods are used to quantitate the remaining (unmetabolized) compound or to spectroscopically study the structures of metabolites. Metabolite structures also can enable synthetic modifications to block metabolism and increase stability. The structure can be modified to block metabolic hotspots, and the new compound can be assayed for its stability. The metabolites themselves also can be synthesized to test them for pharmacological activity, for activity at other targets where side effects may be produced, and for safety testing.