Evaluation of (4-Arylpiperidin-1-yl)cyclopentanecarboxamides As High-Affinity and Long-Residence-Time Antagonists for the CCR2 Receptor

• Published in: ChemMedChem 2015-07, Vol.10 (7), p.1249-1258
• Main Authors: Vilums, Maris, Zweemer, Annelien J. M., Dilanchian, Arian, van Veldhoven, Jacobus P. D., de Vries, Henk, Brussee, Johannes, Saunders, John, Stamos, Dean, Heitman, Laura H., IJzerman, Adriaan P.
• Format: Article
• Language: English
• Subjects: Animals; antagonists; Chemokines; Cyclopentanes - chemical synthesis; Cyclopentanes - chemistry; Cyclopentanes - pharmacology; cytokines; Dose-Response Relationship, Drug; Kinetics; Molecular Conformation; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Receptors, CCR2 - antagonists & inhibitors; Structure-Activity Relationship; structure-affinity relationships; structure-kinetics relationships; Time Factors
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201500058

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. The perfect combo: The structure–affinity relationships (SARs) and structure–kinetics relationships (SKRs) of CCR2 antagonists based on the MK‐0483 scaffold suggests that piperidine should be saturated and at the cis position to a rigidified carboxamide. The affinity can be improved with H‐bond acceptors on the phenyl ring, and a long residence time (tres) results from appropriately sized lipophilic groups or a (3‐methylpiperidin‐4‐yl)benzoic acid moiety.