| Literature DB >> 26210506 |
Julien Louvel1, Dong Guo2, Marjolein Soethoudt2, Tamara A M Mocking2, Eelke B Lenselink2, Thea Mulder-Krieger2, Laura H Heitman2, Adriaan P IJzerman2.
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.Entities:
Keywords: Adenosine A(1) receptor; Extracellular loops; Residence time; Structure-affinity relationships; Structure-kinetics relationships
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Year: 2015 PMID： 26210506 DOI： 10.1016/j.ejmech.2015.07.023
Source DB: PubMed Journal: Eur J Med Chem ISSN： 0223-5234 Impact factor: 6.514