ABSTRACT
To reach the status of marketed drug, a chemical compound must exhibit, besides high affinity and selectivity for the targeted binding site, good pharmacokinetic properties, minimal side effects, and low toxicity. A further requirement is patentability; that is, the compound must have nonobvious chemical alterations compared to previously disclosed compounds. Historically, medicinal chemistry efforts, as illustrated in Fig. I, started from a lead structure that had (typically) poor DMPK (distribution, metabolism, and pharmacokinetic) properties and micromolar affinity. Initial synthetic efforts were aimed at improving the binding affinity (steps l-10 in Fig. 1). Once medium-to low-nanomolar affinity was achieved, DMPK properties were optimized (steps 11-23 in Fig. 1). This process was far from trivial, since one had to preserve the molecular determinants responsible for affinity while modifying the chemical structure to achieve good DMPK properties. This often resulted in reduced binding affinity
Oprea et al.
