Structure-activity relationships of novel, highly potent, selective, and orally active CCR1 antagonists.
Design and synthesis of a series of 3-amino-4-(2-(2-(4-benzylpiperazin-1-yl)-2-oxoethoxy)phenylamino)cyclobutenedione derivatives as novel CCR1 antagonists are described. Structure-activity relationship studies led to the identification of compound 22, which demonstrated potent binding activity, functional antagonism of CCR1 as well as good species cross-reactivity. In addition, compound 22 also showed desirable pharmacokinetic profiles and was selected for in vivo studies in the mouse collagen-induced arthritis model.
Xie
Yun Feng
YF
Department of Chemistry, Tanabe Research Laboratories, Inc., 4540 Towne Centre Court, San Diego, CA 92121, USA.
Lake
Kirk
K
Ligsay
Kathleen
K
Komandla
Mallareddy
M
Sircar
Ila
I
Nagarajan
Gobi
G
Li
Jian
J
Xu
Kui
K
Parise
Jason
J
Schneider
Lisa
L
Huang
Ding
D
Liu
Juping
J
Dines
Kevin
K
Sakurai
Naoki
N
Barbosa
Miguel
M
Jack
Rick
R
D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D001593:Benzyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D003094:Collagen; D003503:Cyclobutanes / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D015195:Drug Design; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C522191:3-amino-4-(2-(2-(4-benzylpiperazin-1-yl)-2-oxoethoxy)phenylamino)cyclobutenedione; D001593:Benzyl Compounds; C515301:Ccr1 protein, mouse; D003503:Cyclobutanes; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D003094:Collagen