Structure鈥揔inetic Relationships鈥擜n Overlooked Parameter in Hit-to-Lead Optimization: A Case of Cyclopentylamines as Chemokine Receptor 2 Antagonists

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：October 10, 2013
• 年：2013
• 卷：56
• 期：19
• 页码：7706-7714
• 全文大小：364K
• 年卷期：v.56,no.19(October 10, 2013)
• ISSN：1520-4804

文摘

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鈥搆inetic relationship (SKR)] next to a traditional structure鈥揳ffinity 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.