Design, synthesis and test of potencial hypolipidemic drugs with a new target

Novel structures will be designed based on experimental and in silico approach, in order to study dependence of drug structure on inhibition of cholesterol biosynthesis in a cell model, and to study transmembrane transport (permeability) of drugs (Caco cells, HEB). New chemical entities (NCEs) with potential inhibitory action on cholesterol biosynthesis will be synthesized in a chemically diversified space. Statins inhibit HMG-CoA reductase in the early phase of cholesterol biosynthesis, while novel derivatives inhibit cholesterol biosynthesis in a later post-squalene phase and do not influence the synthesis of important intermediates of the preceding steps. New compounds will be tested ex vivo in immortal human hepatocytes and in vivo in hyperlipidemic mouse models. Toxicological studies will also be performed. The effect of new derivatives on transcriptome will be studied by microarrays and by real time PCR in cell lines and in tissue from hiperlipidemic animals . Effects of NCEs will be compared to effects of statins. Transgenic animal models of Alzheimer s disease will be used with the aim to prevent the harmful effects of hyperlipidemic diet on specific markers of Alzheimer's disease. In this regard, cognitive behavioral models, quantitative receptor autoradiography, in situ hybridization and/or immunohistochemistry will be applied. The transfer of drugs across the blood-brain-barier will be investigated. Pharmacological behavioral models and other above mentioned techniques will be used to determine the possible direct interaction of new drugs with specific receptors in the brain.