Discovery of CC chemokine receptor-3 (CCR3) antagonists with picomolar potency.
Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.
De Lucca
George V
GV
Bristol-Myers Squibb Company, Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. george.delucca@bms.com
Kim
Ui Tae
UT
Vargo
Brian J
BJ
Duncia
John V
JV
Santella
Joseph B
JB
Gardner
Daniel S
DS
Zheng
Changsheng
C
Liauw
Ann
A
Wang
Zhang
Z
Emmett
George
G
Wacker
Dean A
DA
Welch
Patricia K
PK
Covington
Maryanne
M
Stowell
Nicole C
NC
Wadman
Eric A
EA
Das
Anuk M
AM
Davies
Paul
P
Yeleswaram
Swamy
S
Graden
Danielle M
DM
Solomon
Kimberly A
KA
Newton
Robert C
RC
Trainor
George L
GL
Decicco
Carl P
CP
Ko
Soo S
SS
D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D018938:Caco-2 Cells; D002118:Calcium / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006224:Cricetinae; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004804:Eosinophils / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy / Q000276:immunology; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010539:Permeability; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C500084:1-(2-((3-(4-fluorobenzyl)piperidin-1-yl)methyl)cyclohexyl)-3-(3-acetylphenyl)urea; C515350:CCR3 protein, human; C515351:Ccr3 protein, mouse; D003510:Cyclohexanes; D010671:Phenylurea Compounds; D010880:Piperidines; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D014508:Urea; D002118:Calcium