title: 6-amino-4-oxo-1,3-diphenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl derivatives as a new class of potent inhibitors of Interleukin-8-induced neutrophil chemotaxis.
abstract: A series of 6-amino-4-oxo-1,3-diphenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl derivatives was synthesized. The compounds demonstrated to be novel, potent and selective inhibitors of Interleukin-8-induced human neutrophil chemotaxis. A SAR study was performed by varying the carbonyl function at position 5 and the chain linked to the amino group at position 6 of the scaffold. All the compounds of the series displayed inhibitory activity at nano- or picomolar concentrations against Interleukin-8-driven migration and no activity against fMLP- and C5a-induced chemotaxis. The binding tests of selected compounds on CXCR1 and CXCR2 receptors were negative. The most potent derivative showed in vivo efficacy in a mouse model of Zymosan-induced peritonitis.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Universitá di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy. sara.cesarini@unige.it
authors.forename: Sara
authors.initials: S
authors.lastname: Cesarini
authors.forename: Andrea
authors.initials: A
authors.lastname: Spallarossa
authors.forename: Angelo
authors.initials: A
authors.lastname: Ranise
authors.forename: Olga
authors.initials: O
authors.lastname: Bruno
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Arduino
authors.forename: Maria
authors.initials: M
authors.lastname: Bertolotto
authors.forename: Franco
authors.initials: F
authors.lastname: Dallegri
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Tognolini
authors.forename: Thomas
authors.initials: T
authors.lastname: Gobbetti
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004195:Disease Models, Animal; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D010538:Peritonitis / Q000188:drug therapy; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D016209:Interleukin-8; D011743:Pyrimidines