Synthesis, structure-activity relationship and in vivo antiinflammatory efficacy of substituted dipiperidines as CCR2 antagonists.
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.
Xia
Mingde
M
Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 8 Clarke Drive, Cranbury, New Jersey 08512, USA. mxia@prdus.jnj.com
Hou
Cuifen
C
DeMong
Duane E
DE
Pollack
Scott R
SR
Pan
Meng
M
Brackley
James A
JA
Jain
Nareshkumar
N
Gerchak
Chrissy
C
Singer
Monica
M
Malaviya
Ravi
R
Matheis
Michele
M
Olini
Gil
G
Cavender
Druie
D
Wachter
Michael
M
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
D000894:Anti-Inflammatory Agents, Non-Steroidal; C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; C515336:Ccr2 protein, rat; D010880:Piperidines; D054390:Receptors, CCR2