Structure–Kinetic RelationshipsAn Overlooked Parameter in Hit-to-Lead Optimization: A Case of Cyclopentylamines as Chemokine Receptor 2 Antagonists

• Published in: Journal of medicinal chemistry Vol. 56; no. 19; pp. 7706 - 7714
• Main Authors: Vilums, Maris, Zweemer, Annelien J. M, Yu, Zhiyi, de Vries, Henk, Hillger, Julia M, Wapenaar, Hannah, Bollen, Ilse A. E, Barmare, Farhana, Gross, Raymond, Clemens, Jeremy, Krenitsky, Paul, Brussee, Johannes, Stamos, Dean, Saunders, John, Heitman, Laura H, IJzerman, Adriaan P
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.10.2013; Amer Chemical Soc
• Subjects: Binding, Competitive; Cell Line, Tumor; Chemistry, Medicinal; Cyclopentanes - chemical synthesis; Cyclopentanes - chemistry; Cyclopentanes - pharmacology; Humans; Indans - chemical synthesis; Indans - chemistry; Indans - pharmacology; Indenes - chemical synthesis; Indenes - chemistry; Indenes - pharmacology; Kinetics; Life Sciences & Biomedicine; Ligands; Pharmacology & Pharmacy; Receptors, CCR2 - antagonists & inhibitors; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Tetrahydronaphthalenes - chemical synthesis; Tetrahydronaphthalenes - chemistry; Tetrahydronaphthalenes - pharmacology; MCP-1; BINDING-KINETICS; PHARMACOLOGICAL CHARACTERIZATION; DRUGS; MECHANISMS; MICE; CCR2 ANTAGONISTS; ASSOCIATION; DISCOVERY; INCB3344
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm4011737

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 (K i = 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.