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

publication · 7 years ago
by Adriaan P. IJzerman, Julien Louvel, Johannes Brussee, Dong Guo, Marta Agliardi, Tamara A. M. Mocking, Roland Kars, Tan Phát Pham, Lizi Xia, Henk de Vries, Laura H. Heitman (Leiden University)
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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.

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