Discovery of disubstituted cyclohexanes as a new class of CC chemokine receptor 2 antagonists

Robert J Cherney; Ruowei Mo; Dayton T Meyer; David J Nelson; Yvonne C Lo; Gengjie Yang; Peggy A Scherle; Sandhya Mandlekar; Zelda R Wasserman; Heather Jezak; Kimberly A Solomon; Andrew J Tebben; Percy H Carter; Carl P Decicco

doi:10.1021/jm701488f

Discovery of disubstituted cyclohexanes as a new class of CC chemokine receptor 2 antagonists

J Med Chem. 2008 Feb 28;51(4):721-4. doi: 10.1021/jm701488f. Epub 2008 Jan 31.

Authors

Robert J Cherney, Ruowei Mo, Dayton T Meyer, David J Nelson, Yvonne C Lo, Gengjie Yang, Peggy A Scherle, Sandhya Mandlekar, Zelda R Wasserman, Heather Jezak, Kimberly A Solomon, Andrew J Tebben, Percy H Carter, Carl P Decicco

PMID: 18232650
DOI: 10.1021/jm701488f

Abstract

We describe the design, synthesis, and evaluation of novel disubstituted cyclohexanes as potent CCR2 antagonists. Exploratory SAR studies led to the cis-disubstituted derivative 22, which displayed excellent binding affinity for CCR2 (binding IC50 = 5.1 nM) and potent functional antagonism (calcium flux IC50 = 18 nM and chemotaxis IC 50 = 1 nM). Site-directed mutagenesis studies with 22 suggest the compound is binding near the key receptor residue Glu291, however, 22 is not reliant on Glu291 for its binding affinity.

MeSH terms

Binding, Competitive
Calcium / metabolism
Chemokine CCL2 / metabolism
Chemotaxis, Leukocyte / drug effects
Cyclohexanes / chemical synthesis*
Cyclohexanes / chemistry
Cyclohexanes / pharmacology
Humans
In Vitro Techniques
Leukocytes, Mononuclear / drug effects
Leukocytes, Mononuclear / metabolism
Models, Molecular
Mutagenesis, Site-Directed
Radioligand Assay
Receptors, CCR2 / antagonists & inhibitors*
Receptors, CCR2 / genetics
Stereoisomerism
Structure-Activity Relationship

Substances

Chemokine CCL2
Cyclohexanes
Receptors, CCR2
Calcium