Discovery of 3,5-bis(trifluoromethyl)benzyl L-arylglycinamide based potent CCR2 antagonists.
Systematic modification of a screening lead yielded a class of potent glycinamide based CCR2 antagonists. The best compound (55, (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-{[2-(1-piperidinyl)ethyl]amino}-2-(3-thienyl)acetamide) displayed good binding affinity (IC50=30 and 39 nM) toward human monocytes and CHO cell expressing human CCR2b, respectively. Functionally, it blocked MCP-1 (CCL2)-induced calcium mobilization (IC50=50 nM) and chemotaxis mediated through the CCR2 receptor (9.6 nM). It is selective against other chemokine receptors tested.
Yang
Lihu
L
Merck Research Laboratories, Rahway, NJ 07065-0900, USA. lihu_yang@merck.com
Zhou
Changyou
C
Guo
Liangqin
L
Morriello
Gregori
G
Butora
Gabor
G
Pasternak
Alexander
A
Parsons
William H
WH
Mills
Sander G
SG
MacCoss
Malcolm
M
Vicario
Pasquale P
PP
Zweerink
Hans
H
Ayala
Julia M
JM
Goyal
Shefali
S
Hanlon
William A
WA
Cascieri
Margaret A
MA
Springer
Marty S
MS
D000818:Animals; D001665:Binding Sites; D016466:CHO Cells / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006224:Cricetinae; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects*; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism
C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; C018556:glycine amide; D002118:Calcium; D005998:Glycine