Synthesis and evaluation of cis-3,4-disubstituted piperidines as potent CC chemokine receptor 2 (CCR2) antagonists.
A series of cis-3,4-disubstituted piperidines was synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. Compound 24 emerged with an attractive profile, possessing excellent binding (CCR2 IC(50)=3.4 nM) and functional antagonism (calcium flux IC(50)=2.0 nM and chemotaxis IC(50)=5.4 nM). Studies to explore the binding of these piperidine analogs utilized a key CCR2 receptor mutant (E291A) with compound 14 and revealed a significant reliance on Glu291 for binding.
Cherney
Robert J
RJ
Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA. robert.cherney@bms.com
Nelson
David J
DJ
Lo
Yvonne C
YC
Yang
Gengjie
G
Scherle
Peggy A
PA
Jezak
Heather
H
Solomon
Kimberly A
KA
Carter
Percy H
PH
Decicco
Carl P
CP
D020650:Combinatorial Chemistry Techniques; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D010880:Piperidines; D054390:Receptors, CCR2; D018698:Glutamic Acid