title: Discovery of 3,5-bis(trifluoromethyl)benzyl L-arylglycinamide based potent CCR2 antagonists.
abstract: 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.
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065-0900, USA. lihu_yang@merck.com
authors.forename: Lihu
authors.initials: L
authors.lastname: Yang
authors.forename: Changyou
authors.initials: C
authors.lastname: Zhou
authors.forename: Liangqin
authors.initials: L
authors.lastname: Guo
authors.forename: Gregori
authors.initials: G
authors.lastname: Morriello
authors.forename: Gabor
authors.initials: G
authors.lastname: Butora
authors.forename: Alexander
authors.initials: A
authors.lastname: Pasternak
authors.forename: William H
authors.initials: WH
authors.lastname: Parsons
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacCoss
authors.forename: Pasquale P
authors.initials: PP
authors.lastname: Vicario
authors.forename: Hans
authors.initials: H
authors.lastname: Zweerink
authors.forename: Julia M
authors.initials: JM
authors.lastname: Ayala
authors.forename: Shefali
authors.initials: S
authors.lastname: Goyal
authors.forename: William A
authors.initials: WA
authors.lastname: Hanlon
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Cascieri
authors.forename: Marty S
authors.initials: MS
authors.lastname: Springer
mesh_terms: 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
chemical_list: C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; C018556:glycine amide; D002118:Calcium; D005998:Glycine