1. 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
- Author
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Sara Cesarini, Maria Bertolotto, Thomas Gobbetti, Nicoletta Arduino, Angelo Ranise, Franco Dallegri, Olga Bruno, Elisabetta Barocelli, Andrea Spallarossa, and Massimiliano Tognolini
- Subjects
Neutrophils ,Stereochemistry ,Neutrophile ,Clinical Biochemistry ,Carboxylic Acids ,Pharmaceutical Science ,Peritonitis ,Biochemistry ,Chemical synthesis ,Mice ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,Animals ,CXC chemokine receptors ,Interleukin 8 ,Receptor ,Molecular Biology ,Interleukin-8, Inhibitors, Neutrophil, Chemotaxis, Peritonitis ,Inhibitors ,Chemistry ,Chemotaxis ,Interleukin-8 ,Neutrophil ,Organic Chemistry ,In vitro ,Chemotaxis, Leukocyte ,Disease Models, Animal ,Pyrimidines ,Molecular Medicine - 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.
- Published
- 2009
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