title: Pharmacological characterization of Sch527123, a potent allosteric CXCR1/CXCR2 antagonist.
abstract: In neutrophils, growth-related protein-alpha (CXCL1) and interleukin-8 (CXCL8), are potent chemoattractants (Cytokine 14:27-36, 2001; Biochemistry 42:2874-2886, 2003) and can stimulate myeloperoxidase release via activation of the G protein-coupled receptors CXCR1 and CXCR2. The role of CXCR1 and CXCR2 in the pathogenesis of inflammatory responses has encouraged the development of small molecule antagonists for these receptors. The data presented herein describe the pharmacology of 2-hydroxy-N,N-dimethyl-3-{2-[[(R)-1-(5-methyl-furan-2-yl)-propyl]amino]-3,4-dioxo-cyclobut-1-enylamino}-benzamide (Sch527123), a novel antagonist of both CXCR1 and CXCR2. Sch527123 inhibited chemokine binding to (and activation of) these receptors in an insurmountable manner and, as such, is categorized as an allosteric antagonist. Sch527123 inhibited neutrophil chemotaxis and myeloperoxidase release in response to CXCL1 and CXCL8 but had no effect on the response of these cells to C5a or formyl-methionyl-leucyl-phenylalanine. The pharmacological specificity of Sch527123 was confirmed by testing in a diversity profile against a panel of enzymes, channels, and receptors. To measure compound affinity, we characterized [(3)H]Sch527123 in both equilibrium and nonequilibrium binding analyses. Sch527123 binding to CXCR1 and CXCR2 was both saturable and reversible. Although Sch527123 bound to CXCR1 with good affinity (K(d) = 3.9 +/- 0.3 nM), the compound is CXCR2-selective (K(d) = 0.049 +/- 0.004 nM). Taken together, our data show that Sch527123 represents a novel, potent, and specific CXCR2 antagonist with potential therapeutic utility in a variety of inflammatory conditions.
authors.affiliation: Department of Inflammation, K15 E332C-3945, Schering-Plough Research Institute, 2015 Galloping Hill Rd, Kenilworth, NJ 07033-0539, USA.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Gonsiorek
authors.forename: Xuedong
authors.initials: X
authors.lastname: Fan
authors.forename: David
authors.initials: D
authors.lastname: Hesk
authors.forename: James
authors.initials: J
authors.lastname: Fossetta
authors.forename: Hongchen
authors.initials: H
authors.lastname: Qiu
authors.forename: James
authors.initials: J
authors.lastname: Jakway
authors.forename: Motasim
authors.initials: M
authors.lastname: Billah
authors.forename: Michael
authors.initials: M
authors.lastname: Dwyer
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chao
authors.forename: Gregory
authors.initials: G
authors.lastname: Deno
authors.forename: Art
authors.initials: A
authors.lastname: Taveras
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lundell
authors.forename: R William
authors.initials: RW
authors.lastname: Hipkin
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D015936:Complement C5a / Q000494:pharmacology; D003503:Cyclobutanes / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C516686:2-hydroxy-N,N-dimethyl-3-(2-((1-(5-methylfuran-2-yl)propyl)amino)-3,4-dioxocyclobut-1-enylamino)benzamide; D001549:Benzamides; D003503:Cyclobutanes; D016209:Interleukin-8; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009240:N-Formylmethionine Leucyl-Phenylalanine; D015936:Complement C5a