title: Discovery of trisubstituted cyclohexanes as potent CC chemokine receptor 2 (CCR2) antagonists.
abstract: A series of trisubstituted cyclohexanes was designed, synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the identification of two distinct substitution patterns about the cyclohexane ring as potent and selective CCR2 antagonists. Compound 36 exhibited excellent binding (CCR2 IC(50)=2.4 nM) and functional antagonism (calcium flux IC(50)=2.0 nM and chemotaxis IC(50)=5.1 nM).
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA. robert.cherney@bms.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cherney
authors.forename: John B
authors.initials: JB
authors.lastname: Brogan
authors.forename: Ruowei
authors.initials: R
authors.lastname: Mo
authors.forename: Yvonne C
authors.initials: YC
authors.lastname: Lo
authors.forename: Gengjie
authors.initials: G
authors.lastname: Yang
authors.forename: Persymphonie B
authors.initials: PB
authors.lastname: Miller
authors.forename: Peggy A
authors.initials: PA
authors.lastname: Scherle
authors.forename: Bruce F
authors.initials: BF
authors.lastname: Molino
authors.forename: Percy H
authors.initials: PH
authors.lastname: Carter
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
mesh_terms: D001665:Binding Sites; D002118:Calcium / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018932:Chemokine CCL2 / Q000737:chemistry; D002633:Chemotaxis; D003510:Cyclohexanes / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D015394:Molecular Structure; D011485:Protein Binding; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D003510:Cyclohexanes; D054390:Receptors, CCR2; D002118:Calcium