title: Synthesis, structure-activity relationship and in vivo antiinflammatory efficacy of substituted dipiperidines as CCR2 antagonists.
abstract: A series of substituted dipiperidine compounds have been synthesized and identified as selective CCR2 antagonists. Combining the most favorable substituents led to the discovery of remarkably potent CCR2 antagonists displaying IC50 values in the nanomolar range. Compound 7a had outstanding selectivity over CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, and CCR8 and showed excellent efficacy in adjuvant-induced arthritis model, collagen-induced arthritis model, and allergic asthma model.
authors.affiliation: Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 8 Clarke Drive, Cranbury, New Jersey 08512, USA. mxia@prdus.jnj.com
authors.forename: Mingde
authors.initials: M
authors.lastname: Xia
authors.forename: Cuifen
authors.initials: C
authors.lastname: Hou
authors.forename: Duane E
authors.initials: DE
authors.lastname: DeMong
authors.forename: Scott R
authors.initials: SR
authors.lastname: Pollack
authors.forename: Meng
authors.initials: M
authors.lastname: Pan
authors.forename: James A
authors.initials: JA
authors.lastname: Brackley
authors.forename: Nareshkumar
authors.initials: N
authors.lastname: Jain
authors.forename: Chrissy
authors.initials: C
authors.lastname: Gerchak
authors.forename: Monica
authors.initials: M
authors.lastname: Singer
authors.forename: Ravi
authors.initials: R
authors.lastname: Malaviya
authors.forename: Michele
authors.initials: M
authors.lastname: Matheis
authors.forename: Gil
authors.initials: G
authors.lastname: Olini
authors.forename: Druie
authors.initials: D
authors.lastname: Cavender
authors.forename: Michael
authors.initials: M
authors.lastname: Wachter
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy; D001249:Asthma / Q000188:drug therapy; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D008297:Male; D051379:Mice; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; C515336:Ccr2 protein, rat; D010880:Piperidines; D054390:Receptors, CCR2