Motivation

• Late-stage attrition due to obviously bad physicochemical properties has been reduced by application of rules-ofthumb like Lipinski’s Rule of Five.
• Failure due to lack of efficacy remains a major issue. This can be due to a poor choice of target, but can also reflect poor pharmacokinetics (PK).
• Combinations of physicochemical properties may be problematic even when each individual property seems acceptable.
• This can make it hard to know which property to modify next, e.g., decreasing hydrophobicity to try to address problems with solubility and metabolism is likely to decrease absorption as well.
• Is there a way to explore the pharmacokinetic landscape before enough compound has been synthesized to assess its PK behavior in vivo?

Structure Activity Relationships UKQSAR/MGMS Joint Conference 2018, April 11-12, 2018, Cardiff, Wales

By Robert D. Clark