Novel sulfone-containing di- and trisubstituted cyclohexanes as potent CC chemokine receptor 2 (CCR2) antagonists.
Potent sulfone-containing di- and trisubstituted cyclohexanes were synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the trisubstituted derivative 54, which exhibited excellent binding (CCR2 IC(50)=1.3nM) and functional antagonism (calcium flux IC(50)=0.5nM and chemotaxis IC(50)=0.2nM). The superiority of the trisubstituted scaffold was rationalized to be the result of a conformational rigidification, which provided insight into the bioactive conformation of this chemotype.
Cherney
Robert J
RJ
Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, United States. robert.cherney@bms.com
Mo
Ruowei
R
Meyer
Dayton T
DT
Voss
Matthew E
ME
Lo
Yvonne C
YC
Yang
Gengjie
G
Miller
Persymphonie B
PB
Scherle
Peggy A
PA
Tebben
Andrew J
AJ
Carter
Percy H
PH
Decicco
Carl P
CP
D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry*
D003510:Cyclohexanes; D054390:Receptors, CCR2; D013450:Sulfones