title: Pyrido-pyrimidine derivative CYC10424 inhibits glycosaminoglycan changes on vascular smooth muscle-derived proteoglycans and reduces lipoprotein binding.
abstract: Cardiovascular disease is a major cause of mortality with the underlying process being atherosclerosis. Modified proteoglycans bind low-density lipoproteins (LDL), a critical initial step in the atherosclerotic cascade, representing a potential therapeutic target. Platelet-derived growth factor (PDGF) stimulates proteoglycan synthesis and is strongly implicated in atherogenesis. In human vascular smooth muscle cells (VSMCs), CYC10424 (Cytopia Research Ltd), a pyrido-pyrimidine derivative, dose-dependently decreased PDGF-mediated radiolabel incorporation into proteoglycans associated with an increase in electrophoretic mobility by SDS-PAGE. PDGF stimulated increases in both chemically-cleaved and xyloside-associated glycosaminoglycan (GAG) chain size, which were inhibited in the presence of CYC10424 by size exclusion chromatography (Sepharose CL-6B). CYC10424 treatment inhibited the PDGF effect to increase the 6:4 position sulfation ratio of monosulfated disaccharides by fluorophore-assisted carbohydrate electrophoresis. Proteoglycans derived from cells treated with CYC10424 had a decreased binding affinity and capacity to human LDL by gel mobility shift assay. CYC10424 and related compounds are possible candidates as therapeutic agents for the prevention of lipid deposition as characteristic of diseases such as atherosclerosis.
authors.affiliation: Cell Biology of Diabetes Laboratory, Baker Heart Research Institute, Melbourne, Victoria, Australia.
authors.forename: Mandy L
authors.initials: ML
authors.lastname: Ballinger
authors.forename: Narin
authors.initials: N
authors.lastname: Osman
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Wilks
authors.forename: Stephen
authors.initials: S
authors.lastname: Su
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Burns
authors.forename: Xianyong
authors.initials: X
authors.lastname: Bu
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Little
mesh_terms: D050197:Atherosclerosis / Q000378:metabolism / Q000517:prevention & control; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D024202:Electrophoretic Mobility Shift Assay; D006025:Glycosaminoglycans / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D015394:Molecular Structure; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011485:Protein Binding; D011509:Proteoglycans / Q000378:metabolism*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D006025:Glycosaminoglycans; D008077:Lipoproteins, LDL; C534914:N-(4-methyl-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)phenyl)-N'-phenylurea; D010671:Phenylurea Compounds; D010982:Platelet-Derived Growth Factor; D011509:Proteoglycans; D011743:Pyrimidines