Structure-kinetic relationships--an overlooked parameter in hit-to-lead optimization: a case of cyclopentylamines as chemokine receptor 2 antagonistsVilums, M., Zweemer, A. J. M., Yu, Z., de Vries, H., Hillger, J. M., Wapenaar, H., Bollen, I. A. E., Barmare, F., Gross, R., Clemens, J., Krenitsky, P., Brussee, J., Stamos, D., Saunders, J., Heitman, L. H. & IJzerman, A. P., 10-Oct-2013, In : Journal of Medicinal Chemistry. 56, 19, p. 7706-7714 9 p.
Research output: Contribution to journal › Article › Academic › peer-review
Preclinical models of inflammatory diseases (e.g., neuropathic pain, rheumatoid arthritis, and multiple sclerosis) have pointed to a critical role of the chemokine receptor 2 (CCR2) and chemokine ligand 2 (CCL2). However, one of the biggest problems of high-affinity inhibitors of CCR2 is their lack of efficacy in clinical trials. We report a new approach for the design of high-affinity and long-residence-time CCR2 antagonists. We developed a new competition association assay for CCR2, which allows us to investigate the relation of the structure of the ligand and its receptor residence time [i.e., structure-kinetic relationship (SKR)] next to a traditional structure-affinity relationship (SAR). By applying combined knowledge of SAR and SKR, we were able to re-evaluate the hit-to-lead process of cyclopentylamines as CCR2 antagonists. Affinity-based optimization yielded compound 1 with good binding (Ki = 6.8 nM) but very short residence time (2.4 min). However, when the optimization was also based on residence time, the hit-to-lead process yielded compound 22a, a new high-affinity CCR2 antagonist (3.6 nM), with a residence time of 135 min.
|Number of pages||9|
|Journal||Journal of Medicinal Chemistry|
|Publication status||Published - 10-Oct-2013|
- CCR2 ANTAGONISTS, PHARMACOLOGICAL CHARACTERIZATION, BINDING-KINETICS, DISCOVERY, ASSOCIATION, MECHANISMS, INCB3344, DRUGS, MCP-1, MICE