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Evaluation of (4‐Arylpiperidin‐1‐yl)cyclopentanecarboxamides As High‐Affinity and Long‐Residence‐Time Antagonists for the CCR2 Receptor
Author(s) -
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.
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500058
Subject(s) - receptor , residence , pharmacology , ccr2 , chemistry , residence time (fluid dynamics) , computational biology , stereochemistry , medicine , biology , chemokine receptor , biochemistry , sociology , engineering , demography , geotechnical engineering , chemokine
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: K i =2.8 n M , residence time ( t res )=243 min; 3‐ i Pr: K i =3.6 n M , t res =266 min]. Alternatively, additional substituents and further optimization of the molecule, while keeping a carboxylic acid at the 3‐position, can also prolong t res ; this was most prominently observed in MK‐0483 ( K i =1.2 n M , t res =724 min) and a close analogue ( K i =7.8 n M ) with a short residence time.