Agonists for the Adenosine A(1) Receptor with Tunable Residence Time. A Case for Nonribose 4-Amino-6-aryl-5-cyano-2-thiopyrimidines

作者：Louvel Julien^*; Guo Dong; Agliardi Marta; Mocking Tamara A M; Kars Roland; Tan Phat Pham; Xia Lizi; de Vries Henk; Brussee Johannes; Heitman Laura H; IJzerman Adriaan P

来源：Journal of Medicinal Chemistry, 2014, 57(8): 3213-3222.

DOI：10.1021/jm401643m

We report the synthesis and evaluation of previously unreported 4-amino-6-aryl-5-cyano-2-thiopyrimidines as selective human adenosine A(1) receptor (hA(1)AR) 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.

• 出版日期2014-4-24