On-rate based optimization of structure–kinetic relationship – surfing the kinetic map

• We suggest using on-rates as monitoring parameter for SKR.
• The overall range for kon optimization is estimated to cover 102–108 m−1 s−1.
• For single targets the variability of kon within a compound series can be limited.
• Long residence times can be achieved by affinity optimization despite fast on-rates.
• Conformational rearrangements and desolvation processes can influence on-rates.

In the lead discovery process residence time has become an important parameter for the identification and characterization of the most efficacious compounds in vivo. To enable the success of compound optimization by medicinal chemistry toward a desired residence time the understanding of structure–kinetic relationship (SKR) is essential. This article reviews various approaches to monitor SKR and suggests using the on-rate as the key monitoring parameter. The literature is reviewed and examples of compound series with low variability as well as with significant changes in on-rates are highlighted. Furthermore, findings of kinetic on-rate changes are presented and potential underlying rationales are discussed.