The objective of this drug discovery phase is to synthesize lead compounds, new analogs with improved potency, reduced off-target activities, and physiochemical/metabolic properties suggestive of reasonable in vivo pharmacokinetics. This optimization is accomplished through chemical modification of the hit structure, with modifications chosen by employing knowledge of the structure–activity relationship (SAR) as well as structure-based design if structural information about the target is available.
Lead optimization is concerned with experimental testing and confirmation of the compound based on animal efficacy models and ADMET (in vitro and in situ) tools that may be followed by target identification and target validation.