CCR3 antagonists: a potential new therapy for the treatment of asthma. Discovery and structure-activity relationships.
CCR3 antagonist leads with IC(50) values in the microM range were converted into low nM binding compounds that displayed in vitro inhibition of human eosinophil chemotaxis induced by human eotaxin. In particular, 4-benzylpiperidin-1-yl-n-propylureas and erythro-3-(4-benzyl-2-(alpha-hydroxyalkyl)piperidin-1-yl)-n-propylureas (obtained via Beak reaction of N-BOC-4-benzylpiperidine) exhibited single digit nanomolar IC(50) values for CCR3.
Wacker
Dean A
DA
Bristol-Myers Squibb Company, Experimental Station, PO Box 80336, Wilmington, DE 19880-0336, USA. dean.wacker@bms.com
Santella
Joseph B
JB
Gardner
Daniel S
DS
Varnes
Jeffrey G
JG
Estrella
Melissa
M
DeLucca
George V
GV
Ko
Soo S
SS
Tanabe
Keiichi
K
Watson
Paul S
PS
Welch
Patricia K
PK
Covington
Maryanne
M
Stowell
Nicole C
NC
Wadman
Eric A
EA
Davies
Paul
P
Solomon
Kimberly A
KA
Newton
Robert C
RC
Trainor
George L
GL
Friedman
Steven M
SM
Decicco
Carl P
CP
Duncia
John V
JV
D000478:Alkylation; D000577:Amides / Q000737:chemistry / Q000378:metabolism; D018927:Anti-Asthmatic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D010880:Piperidines / Q000737:chemistry; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D018927:Anti-Asthmatic Agents; C515456:CCL11 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D008024:Ligands; D010880:Piperidines; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D002118:Calcium