Universiteit Leiden

nl en


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

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.

Vilums, M.; Zweemer, A.J.; Dilanchian, A.; Van Veldhoven, J.P.; De Vries, H.; Brussee, J.; Saunders, J.; Stamos, D.; Heitman, L.H.; IJzerman, A.P.
01 June 2015
Online publication

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.

This website uses cookies.  More information.