Discovery of N-propylurea 3-benzylpiperidines as selective CC chemokine receptor-3 (CCR3) antagonists.
The discovery of novel and selective small molecule antagonists of the CC Chemokine Receptor-3 (CCR3) is presented. Simple conversion from a 4- to 3-benzylpiperidine gave improved selectivity for CCR3 over the serotonin 5HT(2A) receptor. Chiral resolution and exploration of mono- and disubstitution of the N-propylurea resulted in several 3-benzylpiperidine N-propylureas with CCR3 binding IC(50)s under 5 nM. Data from in vitro calcium mobilization and chemotaxis assays for these compounds ranged from high picomolar to low nanomolar EC(50)s and correlated well with antagonist binding IC(50)s.
Varnes
Jeffrey G
JG
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08542-5400, USA.
Gardner
Daniel S
DS
Santella
Joseph B
JB
Duncia
John V
JV
Estrella
Melissa
M
Watson
Paul S
PS
Clark
Cheryl M
CM
Ko
Soo S
SS
Welch
Patricia
P
Covington
Maryanne
M
Stowell
Nicole
N
Wadman
Eric
E
Davies
Paul
P
Solomon
Kimberley
K
Newton
Robert C
RC
Trainor
George L
GL
Decicco
Carl P
CP
Wacker
Dean A
DA
D000818:Animals; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*
D010880:Piperidines; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; C017680:propylurea; D014508:Urea