Discovery of trisubstituted cyclohexanes as potent CC chemokine receptor 2 (CCR2) antagonists

Robert J Cherney; John B Brogan; Ruowei Mo; Yvonne C Lo; Gengjie Yang; Persymphonie B Miller; Peggy A Scherle; Bruce F Molino; Percy H Carter; Carl P Decicco

doi:10.1016/j.bmcl.2008.12.062

Discovery of trisubstituted cyclohexanes as potent CC chemokine receptor 2 (CCR2) antagonists

Bioorg Med Chem Lett. 2009 Feb 1;19(3):597-601. doi: 10.1016/j.bmcl.2008.12.062. Epub 2008 Dec 24.

Authors

Robert J Cherney¹, John B Brogan, Ruowei Mo, Yvonne C Lo, Gengjie Yang, Persymphonie B Miller, Peggy A Scherle, Bruce F Molino, Percy H Carter, Carl P Decicco

Affiliation

¹ Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA. [email protected]

PMID: 19131247
DOI: 10.1016/j.bmcl.2008.12.062

Abstract

A series of trisubstituted cyclohexanes was designed, synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the identification of two distinct substitution patterns about the cyclohexane ring as potent and selective CCR2 antagonists. Compound 36 exhibited excellent binding (CCR2 IC(50)=2.4 nM) and functional antagonism (calcium flux IC(50)=2.0 nM and chemotaxis IC(50)=5.1 nM).

MeSH terms

Binding Sites
Calcium / chemistry
Chemistry, Pharmaceutical / methods*
Chemokine CCL2 / chemistry
Chemotaxis
Cyclohexanes / chemistry
Drug Design
Humans
Inhibitory Concentration 50
Models, Chemical
Molecular Structure
Protein Binding
Receptors, CCR2 / antagonists & inhibitors*
Receptors, CCR2 / chemistry*
Structure-Activity Relationship

Substances

CCL2 protein, human
Chemokine CCL2
Cyclohexanes
Receptors, CCR2
Calcium