title: Synthesis and structure-activity relationships of heteroaryl substituted-3,4-diamino-3-cyclobut-3-ene-1,2-dione CXCR2/CXCR1 receptor antagonists.
abstract: 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.
authors.affiliation: Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Younong
authors.initials: Y
authors.lastname: Yu
authors.forename: Michael P
authors.initials: MP
authors.lastname: Dwyer
authors.forename: Jianping
authors.initials: J
authors.lastname: Chao
authors.forename: Cynthia
authors.initials: C
authors.lastname: Aki
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chao
authors.forename: Biju
authors.initials: B
authors.lastname: Purakkattle
authors.forename: Diane
authors.initials: D
authors.lastname: Rindgen
authors.forename: Richard
authors.initials: R
authors.lastname: Bond
authors.forename: Rosemary
authors.initials: R
authors.lastname: Mayer-Ezel
authors.forename: James
authors.initials: J
authors.lastname: Jakway
authors.forename: Hongchen
authors.initials: H
authors.lastname: Qiu
authors.forename: R William
authors.initials: RW
authors.lastname: Hipkin
authors.forename: James
authors.initials: J
authors.lastname: Fossetta
authors.forename: Waldemar
authors.initials: W
authors.lastname: Gonsiorek
authors.forename: Hong
authors.initials: H
authors.lastname: Bian
authors.forename: Xuedong
authors.initials: X
authors.lastname: Fan
authors.forename: Carol
authors.initials: C
authors.lastname: Terminelli
authors.forename: Jay
authors.initials: J
authors.lastname: Fine
authors.forename: Daniel
authors.initials: D
authors.lastname: Lundell
authors.forename: J Robert
authors.initials: JR
authors.lastname: Merritt
authors.forename: Zhenmin
authors.initials: Z
authors.lastname: He
authors.forename: Gaifa
authors.initials: G
authors.lastname: Lai
authors.forename: Minglang
authors.initials: M
authors.lastname: Wu
authors.forename: Arthur
authors.initials: A
authors.lastname: Taveras
mesh_terms: 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
chemical_list: C110624:3-cyclobutene-1,2-dione; D003503:Cyclobutanes; D003959:Diamines; D006571:Heterocyclic Compounds; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B