Synthesis and structure-activity relationships of 3,4-diaminocyclobut-3-ene-1,2-dione CXCR2 antagonists.
A novel series of 3,4-diaminocyclobut-3-ene-1,2-diones was prepared and found to show potent inhibitory activity of CXCR2 binding and IL-8-mediated chemotaxis of a CXCR2-expressing cell line. Microsome stability and Caco2 studies were subsequently used to show that compounds of this chemotype are predicted to have good oral bioavailability and are thus suitable for pharmaceutical development.
Merritt
J Robert
JR
Pharmacopeia Drug Discovery, Inc., 3000 Eastpark Blvd., Cranbury, NJ 08512, USA. bmerritt@pcop.com
Rokosz
Laura L
LL
Nelson
Kingsley H
KH
Kaiser
Bernd
B
Wang
Wei
W
Stauffer
Tara M
TM
Ozgur
Lynne E
LE
Schilling
Adriane
A
Li
Ge
G
Baldwin
John J
JJ
Taveras
Arthur G
AG
Dwyer
Michael P
MP
Chao
Jianping
J
D000284:Administration, Oral; D001682:Biological Availability; D018938:Caco-2 Cells; D003503:Cyclobutanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D003503:Cyclobutanes; D023063:Receptors, Interleukin-8B