CC chemokine receptor-3 (CCR3) antagonists: improving the selectivity of DPC168 by reducing central ring lipophilicity.
DPC168, a benzylpiperidine-substituted aryl urea CCR3 antagonist evaluated in clinical trials, was a relatively potent inhibitor of the 2D6 isoform of cytochrome P-450 (CYP2D6). Replacement of the cyclohexyl central ring with saturated heterocycles provided potent CCR3 antagonists with improved selectivity against CYP2D6. The favorable preclinical profile of DPC168 was maintained in an acetylpiperidine derivative, BMS-570520.
Pruitt
James R
JR
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA.
Batt
Douglas G
DG
Wacker
Dean A
DA
Bostrom
Lori L
LL
Booker
Shon K
SK
McLaughlin
Erin
E
Houghton
Gregory C
GC
Varnes
Jeffrey G
JG
Christ
David D
DD
Covington
Maryanne
M
Das
Anuk M
AM
Davies
Paul
P
Graden
Danielle
D
Kariv
Ilona
I
Orlovsky
Yevgeniya
Y
Stowell
Nicole C
NC
Vaddi
Krishna G
KG
Wadman
Eric A
EA
Welch
Patricia K
PK
Yeleswaram
Swamy
S
Solomon
Kimberly A
KA
Newton
Robert C
RC
Decicco
Carl P
CP
Carter
Percy H
PH
Ko
Soo S
SS
D000818:Animals; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001681:Biological Assay; D002478:Cells, Cultured; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D006801:Humans; D051379:Mice; D002679:Pan troglodytes; D010671:Phenylurea Compounds / Q000737:chemistry* / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C500084:1-(2-((3-(4-fluorobenzyl)piperidin-1-yl)methyl)cyclohexyl)-3-(3-acetylphenyl)urea; C521493:BMS-570520; D001593:Benzyl Compounds; C515350:CCR3 protein, human; C515351:Ccr3 protein, mouse; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D010671:Phenylurea Compounds; D010880:Piperidines; D054397:Receptors, CCR3; D019707:Receptors, Chemokine