2. Academic Validation
  3. Agonists for the adenosine A1 receptor with tunable residence time. A Case for nonribose 4-amino-6-aryl-5-cyano-2-thiopyrimidines

Agonists for the adenosine A1 receptor with tunable residence time. A Case for nonribose 4-amino-6-aryl-5-cyano-2-thiopyrimidines

  • J Med Chem. 2014 Apr 24;57(8):3213-22. doi: 10.1021/jm401643m.
Julien Louvel 1,  Dong Guo,  Marta Agliardi,  Tamara A M Mocking,  Roland Kars,  Tan Phát Pham,  Lizi Xia,  Henk de Vries,  Johannes Brussee,  Laura H Heitman,  Adriaan P Ijzerman
Affiliations

Affiliation

  • 1 Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University , P.O. Box 9502, 2300 RA Leiden, The Netherlands.
PMID: 24669958 DOI: 10.1021/jm401643m
Abstract

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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