title: Structure-kinetics relationships of Capadenoson derivatives as adenosine A1 receptor agonists.
abstract: We report the synthesis and biological evaluation of new derivatives of Capadenoson, a former drug candidate that was previously advanced to phase IIa clinical trials. 19 of the 20 ligands show an affinity below 100 nM at the human adenosine A1 receptor (hA1AR) and display a wide range of residence times at this target (from approx. 5 min (compound 10) up to 132 min (compound 5)). Structure-affinity and structure-kinetics relationships were established, and computational studies of a homology model of the hA1AR revealed crucial interactions for both the affinity and dissociation kinetics of this family of ligands. These results were also combined with global metrics (Ligand Efficiency, cLogP), showing the importance of binding kinetics as an additional way to better select a drug candidate amongst seemingly similar leads.
authors.affiliation: Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands. Electronic address: j.a.louvel@lacdr.leidenuniv.nl.
authors.forename: Julien
authors.initials: J
authors.lastname: Louvel
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: Dong
authors.initials: D
authors.lastname: Guo
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: Marjolein
authors.initials: M
authors.lastname: Soethoudt
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: Tamara A M
authors.initials: TA
authors.lastname: Mocking
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: Eelke B
authors.initials: EB
authors.lastname: Lenselink
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: Thea
authors.initials: T
authors.lastname: Mulder-Krieger
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: Laura H
authors.initials: LH
authors.lastname: Heitman
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: Adriaan P
authors.initials: AP
authors.lastname: IJzerman
mesh_terms: D058907:Adenosine A1 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000631:Aminopyridines / Q000737:chemistry* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D058907:Adenosine A1 Receptor Agonists; D000631:Aminopyridines; D043682:Receptor, Adenosine A1; D013844:Thiazoles; C575871:capadenoson
keywords: Adenosine A(1) receptor; Extracellular loops; Residence time; Structure-affinity relationships; Structure-kinetics relationships