title: Discovery of disubstituted cyclohexanes as a new class of CC chemokine receptor 2 antagonists.
abstract: We describe the design, synthesis, and evaluation of novel disubstituted cyclohexanes as potent CCR2 antagonists. Exploratory SAR studies led to the cis-disubstituted derivative 22, which displayed excellent binding affinity for CCR2 (binding IC50 = 5.1 nM) and potent functional antagonism (calcium flux IC50 = 18 nM and chemotaxis IC 50 = 1 nM). Site-directed mutagenesis studies with 22 suggest the compound is binding near the key receptor residue Glu291, however, 22 is not reliant on Glu291 for its binding affinity.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cherney
authors.forename: Ruowei
authors.initials: R
authors.lastname: Mo
authors.forename: Dayton T
authors.initials: DT
authors.lastname: Meyer
authors.forename: David J
authors.initials: DJ
authors.lastname: Nelson
authors.forename: Yvonne C
authors.initials: YC
authors.lastname: Lo
authors.forename: Gengjie
authors.initials: G
authors.lastname: Yang
authors.forename: Peggy A
authors.initials: PA
authors.lastname: Scherle
authors.forename: Sandhya
authors.initials: S
authors.lastname: Mandlekar
authors.forename: Zelda R
authors.initials: ZR
authors.lastname: Wasserman
authors.forename: Heather
authors.initials: H
authors.lastname: Jezak
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Solomon
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Tebben
authors.forename: Percy H
authors.initials: PH
authors.lastname: Carter
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
mesh_terms: D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011869:Radioligand Assay; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D018932:Chemokine CCL2; D003510:Cyclohexanes; D054390:Receptors, CCR2; D002118:Calcium