The influence and manipulation of acid/base properties in drug discovery.

There is a growing awareness of the importance of acid/base properties in medicinal chemistry research. In many drug classes, ionisable groups are present that make critical interactions with the receptor and are essential for potency. Yet the presence of these groups may cause problems with oral bioavailability, pharmacokinetics, or toxicity. Manipulating pKa values during drug development or applying pro-drug techniques are strategies that can overcome potential deficits in a variety of these areas. Knowledge of drug ionisation states coupled with a consideration of pH-specific cellular environments can be used advantageously to target chemoresistance. As modern drug research ventures into drug candidates that exceed the rule of 5, such exploration requires an understanding of drug acid/base properties and how these factors affect ADMET characteristics.