title: Agonists for the adenosine A1 receptor with tunable residence time. A Case for nonribose 4-amino-6-aryl-5-cyano-2-thiopyrimidines.
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.
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University , P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Julien
authors.initials: J
authors.lastname: Louvel
authors.forename: Dong
authors.initials: D
authors.lastname: Guo
authors.forename: Marta
authors.initials: M
authors.lastname: Agliardi
authors.forename: Tamara A M
authors.initials: TA
authors.lastname: Mocking
authors.forename: Roland
authors.initials: R
authors.lastname: Kars
authors.forename: Tan Phát
authors.initials: TP
authors.lastname: Pham
authors.forename: Lizi
authors.initials: L
authors.lastname: Xia
authors.forename: Henk
authors.initials: H
authors.lastname: de Vries
authors.forename: Johannes
authors.initials: J
authors.lastname: Brussee
authors.forename: Laura H
authors.initials: LH
authors.lastname: Heitman
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: Ijzerman
mesh_terms: D058907:Adenosine A1 Receptor Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D013329:Structure-Activity Relationship
chemical_list: D058907:Adenosine A1 Receptor Agonists; D011743:Pyrimidines