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  • The phenolic hydroxyl group of ezetimibe tolerated various s


    The phenolic hydroxyl group of ezetimibe tolerated various structural modifications (disaccharide, carboxyalkyl and glucuronide) that retained inhibitory activity.13, 14, 15 We conjugated glycylglycine to phenolic hydroxyl group and synthesized ten 1H-pyrrole-2,5-dione derivatives 14a-j successfully. In the preceding work, we screened out compound 3 which had significant effect on the inhibition of total cholesterol cdk9 inhibitor in an orally dosed, cholesterol-fed hamster model. We maintained diphenyl methylene moiety and replaced 2-azetidinone with 1H-pyrrole-2,5-dione as new molecular scaffold to obtain compound 20. At the same time, we introduced diethylamine or sodium sulfonate to the phenolic hydroxyl group and synthesized other compounds 22a-f (Table 2). In this article, we perform a further structural modification of 1H-pyrrole-2,5-dione derivatives to improve the cholesterol absorption inhibitory activity. And the structure-activity relationship (SAR) will be discussed. The most desired compound will be evaluated for their effects on suppressing the lipid accumulation of macrophage and the inflammatory response.
    Results and discussion
    Conclusions The formation of macrophage-derived foam cells is considered to be the crucial aspect of cardiovascular disease, especially in atherosclerosis. Macrophage is present in various stages of atherosclerotic plaque and plays a major role during atherosclerotic lesion, partially through inflammatory response. Excessive accumulation of cholesterol in various types of cells activates the inflammatory response and induces the development and progression of atherosclerosis. In this research, a series of 1H-pyrrole-2,5-dione derivatives were synthesized. In vitro activity evaluation led to the discovery of a number of potent NPC1L1 inhibitors. One of the most potent inhibitors, compound 20 was more active than ezetimibe in the in vitro cholesterol absorption study and displayed the weakest cytotoxicity property in HEK293 and RAW264.7 cell lines and satisfied lipophilicity in a preliminary study. Furthermore, cholesterol uptake inhibitory potency of compound 20 was verified by Cholesterol-D7. Compound 20 also could inhibit macrophage lipid accumulation and reduce the secretion of LDH, MDA, TNF-α and ROS comparable with ezetimibe. This in-depth study indicated that compound 20 could suppress the formation of macrophage-derived foam cells and inflammatory response. So, as a novel and potent cholesterol absorption inhibitor, compound 20 showed the potential of relieving atherosclerosis.
    Experimental section
    Acknowledgements This work was supported by the Natural Science Foundation for Colleges and Universities in Jiangsu Province (No. 11KJB350002), the Natural Science Foundation of Jiangsu Province (No. BK2012422, BK20141015) and the National Natural Science Foundation of China (No. 81202393, 81600159).
    The small intestine mediates the contact between an organism and its nutritional environment, and food impacts both gastrointestinal and systemic gene regulation networks. In , intestinal sensing of early life nutritional cues differentially programs life-long metabolic traits linked to development and longevity via epigenetic mechanisms. In mammals, the extent to which the intestine can sense early life events and translate these into epigenetically adjusted gene expression of key regulators has not been established. However, epidemiology suggests that for dietary cholesterol such a scenario is plausible. Infants fed cholesterol-rich breast milk have lower proatherogenic plasma low-density lipoprotein cholesterol (LDL-C) in adulthood compared with subjects given formula, which is almost devoid of cholesterol. This decrease in LDL-C in formerly breast-fed individuals is clinically relevant, translating into a decreased incidence of cardiovascular disease. Mechanistically, these observations are unexplained, partly because no preclinical model is available that would allow characterization of physiological responses with a satisfactory time resolution and linking these to molecular regulation. Therefore, the aims of our study were as follows: to establish an animal model of reduced dietary cholesterol availability from maternal milk, and to investigate the consequences of decreased milk cholesterol availability early in life for cholesterol metabolism in adult life.