| Autor: |
Xia L; Division of Medicinal Chemistry, LACDR, Leiden University , 2300RA Leiden, The Netherlands., de Vries H; Division of Medicinal Chemistry, LACDR, Leiden University , 2300RA Leiden, The Netherlands., Lenselink EB; Division of Medicinal Chemistry, LACDR, Leiden University , 2300RA Leiden, The Netherlands., Louvel J; Division of Medicinal Chemistry, LACDR, Leiden University , 2300RA Leiden, The Netherlands., Waring MJ, Cheng L, Pahlén S; Medicinal Chemistry, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca , Gothenburg SE-431 83, Sweden., Petersson MJ; Medicinal Chemistry, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca , Gothenburg SE-431 83, Sweden., Schell P, Olsson RI, Heitman LH; Division of Medicinal Chemistry, LACDR, Leiden University , 2300RA Leiden, The Netherlands., Sheppard RJ; Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca , Cambridge SK10 2NA, United Kingdom., IJzerman AP; Division of Medicinal Chemistry, LACDR, Leiden University , 2300RA Leiden, The Netherlands. |
| Abstrakt: |
We report on the synthesis and biological evaluation of a series of 1,2-diarylimidazol-4-carboxamide derivatives developed as CB 1 receptor antagonists. These were evaluated in a radioligand displacement binding assay, a [ 35 S]GTPγS binding assay, and in a competition association assay that enables the relatively fast kinetic screening of multiple compounds. The compounds show high affinities and a diverse range of kinetic profiles at the CB 1 receptor and their structure-kinetic relationships (SKRs) were established. Using the recently resolved hCB 1 receptor crystal structures, we also performed a modeling study that sheds light on the crucial interactions for both the affinity and dissociation kinetics of this family of ligands. We provide evidence that, next to affinity, additional knowledge of binding kinetics is useful for selecting new hCB 1 receptor antagonists in the early phases of drug discovery. |
