Publication

Agonists for the Adenosine A1 Receptor with Tunable Residence Time. A Case for Nonribose 4-Amino-6-aryl-5-cyano-2-thiopyrimidines

Source: J Med Chem, Volume 57, Issue 8, pp. 3213-22 (2014)

Author

Louvel, J.; Guo, D.; Agliardi, M.; Mocking, T.A.M.; Kars, R.; Pham, T.P.; Xia, L.; De Vries, H.; Brussee, J.; Heitman, L.H.; IJzerman, A.P.

Date

26 March 2014

Links

Online publication

We report the synthesis and evaluation of previously unreported 4-amino-6-aryl-5-cyano-2-thiopyrimidines as selective human adenosine A1 receptor (hA1AR) agonists with tunable binding kinetics, this without affecting their nanomolar affinity for the target receptor. They show a very diverse range of kinetic profiles (from 1 min (compound 52) to 1 h (compound 43)), and their structure-affinity relationships (SAR) and structure-kinetics relationships (SKR) were established. When put in perspective with the increasing importance of binding kinetics in drug discovery, these results bring new evidence of the consequences of affinity-only driven selection of drug candidates, that is, the potential elimination of slightly less active compounds that may display preferable binding kinetics.