3,4-Diamino-2,5-thiadiazole-1-oxides as potent CXCR2/CXCR1 antagonists.
A series of novel and potent 3,4-diamino-2,5-thiadiazole-1-oxides were prepared and found to show excellent binding affinities for CXCR2 and CXCR1 receptors and excellent inhibitory activity of Gro-alpha and IL-8 mediated in vitro hPMN MPO release of CXCR2 and CXCR1 expressing cell lines. On the other hand, a closely related 3,4-diamino-2,5-thiadiazole-dioxide did not show functional activity despite its excellent binding affinities for CXCR2 and CXCR1 in membrane binding assays. A detailed SAR has been discussed in these two closely related structures.
Biju
Purakkattle
P
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. purakkattle.biju@spcorp.com
Taveras
Arthur
A
Yu
Younong
Y
Zheng
Junying
J
Chao
Jianhua
J
Rindgen
Diane
D
Jakway
James
J
Hipkin
R William
RW
Fossetta
James
J
Fan
Xuedong
X
Fine
Jay
J
Qiu
Hongchen
H
Merritt
J Robert
JR
Baldwin
John J
JJ
D000818:Animals; D054360:Chemokine CXCL1 / Q000737:chemistry / Q000494:pharmacology; D002630:Chemotactic Factors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D010087:Oxides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
D054360:Chemokine CXCL1; D002630:Chemotactic Factors; D016209:Interleukin-8; D010087:Oxides; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D013830:Thiadiazoles; D009195:Peroxidase