Discovery of disubstituted cyclohexanes as a new class of CC chemokine receptor 2 antagonists.
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.
Cherney
Robert J
RJ
Mo
Ruowei
R
Meyer
Dayton T
DT
Nelson
David J
DJ
Lo
Yvonne C
YC
Yang
Gengjie
G
Scherle
Peggy A
PA
Mandlekar
Sandhya
S
Wasserman
Zelda R
ZR
Jezak
Heather
H
Solomon
Kimberly A
KA
Tebben
Andrew J
AJ
Carter
Percy H
PH
Decicco
Carl P
CP
D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011869:Radioligand Assay; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D018932:Chemokine CCL2; D003510:Cyclohexanes; D054390:Receptors, CCR2; D002118:Calcium