Discovery of trisubstituted cyclohexanes as potent CC chemokine receptor 2 (CCR2) antagonists.
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).
Cherney
Robert J
RJ
Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA. robert.cherney@bms.com
Brogan
John B
JB
Mo
Ruowei
R
Lo
Yvonne C
YC
Yang
Gengjie
G
Miller
Persymphonie B
PB
Scherle
Peggy A
PA
Molino
Bruce F
BF
Carter
Percy H
PH
Decicco
Carl P
CP
D001665:Binding Sites; D002118:Calcium / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018932:Chemokine CCL2 / Q000737:chemistry; D002633:Chemotaxis; D003510:Cyclohexanes / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D015394:Molecular Structure; D011485:Protein Binding; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013329:Structure-Activity Relationship
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D003510:Cyclohexanes; D054390:Receptors, CCR2; D002118:Calcium