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Structure-kinetic relationships--an overlooked parameter in hit-to-lead optimization: a case of cyclopentylamines as chemokine receptor 2 antagonists

Vilums, 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.

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  • Structure-kinetic relationships--an overlooked parameter in hit-to-lead

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DOI

  • Maris Vilums
  • Annelien J. M. Zweemer
  • Zhiyi Yu
  • Henk de Vries
  • Julia M. Hillger
  • Hannah Wapenaar
  • Ilse A. E. Bollen
  • Farhana Barmare
  • Raymond Gross
  • Jeremy Clemens
  • Paul Krenitsky
  • Johannes Brussee
  • Dean Stamos
  • John Saunders
  • Laura H. Heitman
  • Adriaan P. IJzerman

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.

Original languageEnglish
Pages (from-to)7706-7714
Number of pages9
JournalJournal of Medicinal Chemistry
Volume56
Issue number19
Publication statusPublished - 10-Oct-2013
Externally publishedYes

    Keywords

  • CCR2 ANTAGONISTS, PHARMACOLOGICAL CHARACTERIZATION, BINDING-KINETICS, DISCOVERY, ASSOCIATION, MECHANISMS, INCB3344, DRUGS, MCP-1, MICE

ID: 20935860