A novel 2,3-diphenyl-4H-pyrido[1,2-a]pyrimidin-4-one derivative inhibits endothelial cell dysfunction and smooth muscle cell proliferation/activation

• 2-(3,4-Dimethoxyphenyl)-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one inhibits selectively the proliferation of HAoSMCs but not that of HUVECs.
• In HUVECs, 2-(3,4-dimethoxyphenyl)-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one inhibits the VCAM-1 expression but not the COX-2 expression.
• In HAoSMC, 2-(3,4-dimethoxyphenyl)-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one inhibits both the COX-2 expression and the PGE2 release.

Hyper-proliferation and migration of vascular smooth muscle cells and endothelial cell dysfunction are central events in the development of neo-intimal lesions.Pursuing our interest in the synthesis of bioisosters of flavonoids, we studied in depth a novel synthetic 2,3-diphenyl-4H-pyrido[1,2-a]pyrimidin-4-one derivative, examining its effects in vitro on induced-cell proliferation and activation in human aortic smooth muscle cells (HAoSMCs) and in human umbilical vein endothelial cells (HUVECs).Compared with two well known flavonoids, apigenin and quercetin, the novel compound, 2-(3,4-dimethoxyphenyl)-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one, 3, was not toxic for HUVECs, even at high concentrations and for long incubation times, while the two flavonoids were not tolerated, even at concentrations as low as 10 μmol/L. Compound 3 inhibited selectively, and in a concentration-dependent manner, the proliferation of HAoSMCs but not that of HUVECs. In HUVECs, it inhibited the cytokine-induced vascular cell adhesion molecule-1 expression, but not the cyclooxygenase-2 (COX-2) expression. Instead, in HAoSMC, it inhibited the induction of COX-2 expression and the relative release of prostaglandin E2. In addition, it inhibited the transcription of the matrix metalloproteinase-9 and its activity.Thanks to its multiple and tissue-specific function, 2-(3,4-dimethoxyphenyl)-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one might replace or assist the action of current drugs eluted by coronary stents, in order to promote a functional repair of damaged wall.

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