Figure 6. Example of a potential compound discovery paradigm for CNS kinase targets.

Focusing on small-molecule kinase inhibitors with key molecular property characteristics and promising profiles in early-stage pharmacological screens increases the potential for positive outcomes in the subsequent preclinical development of investigational new drugs. This substantially reduces early discovery demands on synthetic chemistry and biology efforts and the later attrition rate in development. Medicinal chemistry refinement takes into consideration molecular properties, suitability for central nervous system (CNS) penetration and ligand activity. Pharmacology-related screens are used to measure brain uptake, assess microsomal stability, determine whether the compound is a cytochrome P450 2D6 (CYP2D6) or CYP3A4 substrate and ensure that there are no adverse effects. HTS, high-throughput screening; IC₅₀, half-maximal inhibitory concentration; SAR, structure–activity relationship.