Synthesis and structure-activity relationships of heteroaryl substituted-3,4-diamino-3-cyclobut-3-ene-1,2-dione CXCR2/CXCR1 receptor antagonists.
Comprehensive SAR studies were undertaken in the 3,4-diaminocyclobut-3-ene-1,2-dione class of CXCR2/CXCR1 receptor antagonists to explore the role of the heterocycle on chemokine receptor binding affinities, functional activity, as well as oral exposure in rat. The nature of the heterocycle as well as the requisite substitution pattern around the heterocycle was shown to have a dramatic effect on the overall biological profile of this class of compounds. The furyl class, particularly the 4-halo adducts, was found to possess superior binding affinities for both the CXCR2 and CXCR1 receptors, functional activity, as well as oral exposure in rat versus other heterocyclic derivatives.
Yu
Younong
Y
Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Dwyer
Michael P
MP
Chao
Jianping
J
Aki
Cynthia
C
Chao
Jianhua
J
Purakkattle
Biju
B
Rindgen
Diane
D
Bond
Richard
R
Mayer-Ezel
Rosemary
R
Jakway
James
J
Qiu
Hongchen
H
Hipkin
R William
RW
Fossetta
James
J
Gonsiorek
Waldemar
W
Bian
Hong
H
Fan
Xuedong
X
Terminelli
Carol
C
Fine
Jay
J
Lundell
Daniel
D
Merritt
J Robert
JR
He
Zhenmin
Z
Lai
Gaifa
G
Wu
Minglang
M
Taveras
Arthur
A
D000818:Animals; D002460:Cell Line; D003503:Cyclobutanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003959:Diamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C110624:3-cyclobutene-1,2-dione; D003503:Cyclobutanes; D003959:Diamines; D006571:Heterocyclic Compounds; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B