Evaluation of (4‐Arylpiperidin‐1‐yl)cyclopentanecarboxamides As High‐Affinity and Long‐Residence‐Time Antagonists for the CCR2 Receptor |
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Authors: | Dr. Maris Vilums Dr. Annelien J. M. Zweemer Arian Dilanchian Jacobus P. D. van Veldhoven Henk de Vries Dr. Johannes Brussee Dr. John Saunders Dr. Dean Stamos Dr. Laura H. Heitman Prof. Adriaan P. IJzerman |
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Affiliation: | 1. Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden (The Netherlands);2. Vertex Pharmaceuticals Inc. 11010 Torreyana Road, San Diego, CA 92121 (USA) |
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Abstract: | Animal models suggest that the chemokine ligand 2/CC‐chemokine receptor 2 (CCL2/CCR2) axis plays an important role in the development of inflammatory diseases. However, CCR2 antagonists have failed in clinical trials because of a lack of efficacy. We previously described a new approach for the design of CCR2 antagonists by the use of structure–kinetics relationships (SKRs). Herein we report new findings on the structure–affinity relationships (SARs) and SKRs of the reference compound MK‐0483, its diastereomers, and its structural analogues as CCR2 antagonists. The SARs of the 4‐arylpiperidine group suggest that lipophilic hydrogen‐bond‐accepting substituents at the 3‐position are favorable. However, the SKRs suggest that a lipophilic group with a certain size is desired [e.g., 3‐Br: Ki=2.8 nM , residence time (tres)=243 min; 3‐iPr: Ki=3.6 nM , tres=266 min]. Alternatively, additional substituents and further optimization of the molecule, while keeping a carboxylic acid at the 3‐position, can also prolong tres; this was most prominently observed in MK‐0483 (Ki=1.2 nM , tres=724 min) and a close analogue (Ki=7.8 nM ) with a short residence time. |
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Keywords: | antagonists cytokines kinetics structure– affinity relationships structure– kinetics relationships |
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