Alpha-aminothiazole-gamma-aminobutanoic amides as potent, small molecule CCR2 receptor antagonists.
A series of racemic and homochiral alpha-aminothiazole-gamma-aminobutyroamides that display high affinities for human and murine CCR2 and functional antagonism by inhibition of monocyte recruitment are described. A representative example is (2S)-2-[2-(acetylamino)-1,3-thiazol-4-yl]-N-[3-methyl-5-(trifluoromethyl)benzyl]-4-(4-phenylpiperidin-1-yl)butanamide, which shows 5 nM affinity for human monocytes and CHO cells expressing the human CCR2b receptor. It also inhibited MCP-1 initiated chemotaxis of human monocytes with an IC50 of 0.69 nM.
Zhou
Changyou
C
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. changyou_zhou@merck.com
Guo
Liangqin
L
Parsons
William H
WH
Mills
Sander G
SG
MacCoss
Malcolm
M
Vicario
Pasquale P
PP
Zweerink
Hans
H
Cascieri
Margaret A
MA
Springer
Martin S
MS
Yang
Lihu
L
D000818:Animals; D016466:CHO Cells; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008566:Membranes / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C111835:CCL2 protein, human; C515334:CCR2 protein, human; C515336:Ccr2 protein, rat; D018932:Chemokine CCL2; D007202:Indicators and Reagents; D064729:Neurokinin-1 Receptor Antagonists; D054390:Receptors, CCR2; D019707:Receptors, Chemokine