title: 3,4-Diamino-2,5-thiadiazole-1-oxides as potent CXCR2/CXCR1 antagonists.
abstract: 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.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. purakkattle.biju@spcorp.com
authors.forename: Purakkattle
authors.initials: P
authors.lastname: Biju
authors.forename: Arthur
authors.initials: A
authors.lastname: Taveras
authors.forename: Younong
authors.initials: Y
authors.lastname: Yu
authors.forename: Junying
authors.initials: J
authors.lastname: Zheng
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chao
authors.forename: Diane
authors.initials: D
authors.lastname: Rindgen
authors.forename: James
authors.initials: J
authors.lastname: Jakway
authors.forename: R William
authors.initials: RW
authors.lastname: Hipkin
authors.forename: James
authors.initials: J
authors.lastname: Fossetta
authors.forename: Xuedong
authors.initials: X
authors.lastname: Fan
authors.forename: Jay
authors.initials: J
authors.lastname: Fine
authors.forename: Hongchen
authors.initials: H
authors.lastname: Qiu
authors.forename: J Robert
authors.initials: JR
authors.lastname: Merritt
authors.forename: John J
authors.initials: JJ
authors.lastname: Baldwin
mesh_terms: 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
chemical_list: D054360:Chemokine CXCL1; D002630:Chemotactic Factors; D016209:Interleukin-8; D010087:Oxides; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D013830:Thiadiazoles; D009195:Peroxidase