Inhibitors of tissue-nonspecific alkaline phosphatase (TNAP): from hits to leads.

The optimization of active hits, commonly derived from high-throughput screening campaigns (see Chapters 2 and 4), into promising small-molecule lead compounds is one of the fundamental steps in early drug discovery. Directions taken during this stage can have important consequences reaching through lead optimization into preclinical development and beyond. Considering the ever-increasing costs of preclinical as well as clinical development phases (DiMasi et al., J Health Econ 22:151-185, 2003) the choices made at the early stages of drug discovery can have a real impact on the likelihood of the best lead becoming a viable candidate (Bleicher et al., Nat Rev Drug Discov 2:369-378, 2003). Thus it is important to utilize proven and robust methodologies to turn promising hits into suitable lead series with propitious characteristics. Here, we describe such an approach using the example of a tissue-nonspecific alkaline phosphatase (see Chapter 3) inhibitor developed in our group (Sidique et al., Bioorg Med Chem Lett 19:222-225, 2009).