Details

Autor(en) / Beteiligte

• Louvel, Julien
• Guo, Dong
• Soethoudt, Marjolein
• Mocking, Tamara A.M.
• Lenselink, Eelke B.
• Mulder-Krieger, Thea
• Heitman, Laura H.
• IJzerman, Adriaan P.

Titel

Structure-kinetics relationships of Capadenoson derivatives as adenosine A1 receptor agonists

Ist Teil von

• European journal of medicinal chemistry, 2015-08, Vol.101, p.681-691

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2015

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •19 new Capadenoson derivatives synthesized.•Affinity and functional data reported at hA1 adenosine receptor.•Structure-affinity and structure-kinetics relationships studied.•New hit identified with longer residence time than Capadenoson.•Docking studies in ligand-optimized homology model to rationalize binding kinetics.