One of the greatest challenges with successful pharmaceutical treatments of central nervous system (CNS) diseases is the delivery of drugs into their target sites with appropriate concentrations. For example, the physically tight blood-brain barrier (BBB) effectively blocks compounds from penetrating into the brain, also by the action of metabolizing enzymes and efflux transport mechanisms. However, many endogenous compounds, including both smaller compounds and macromolecules, like amino acids, sugars, vitamins, nucleosides, hormones, steroids, and electrolytes, have their peculiar internalization routes across the BBB. These delivery mechanisms, namely carrier-mediated transport and receptor-mediated transcytosis have been utilized to some extent in brain-targeted drug development. The incomplete knowledge of the BBB and the smaller than a desirable number of chemical tools have hindered the development of successful brain-targeted pharmaceutics. This review discusses the recent advancements achieved in the field from the point of medicinal chemistry view and discusses how brain drug delivery can be improved in the future.

Charles River Discovery Research Services Finland Oy Neulaniementie 4 70210 Kuopio Finland

Department of Bioinorganic Chemistry Medical University of Lodz Medical University of Lodz ul Muszyńskiego1 90 151 Lodz Poland

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo Namesti 542 2 160 00 Prague Czech Republic

Laboratory of Bioanalysis Department of Pharmaceutical Chemistry Drug Analysis and Radiopharmacy Medical University of Lodz ul Muszyńskiego1 90 151 Lodz Poland

School of Pharmacy Faculty of Health Sciences University of Eastern Finland Yliopistonranta 1C POB 1627 70211 Kuopio Finland

Students Research Group Laboratory of Bioanalysis Department of Pharmaceutical Chemistry Drug Analysis and Radiopharmacy Medical University of Lodz ul Muszyńskiego 1 90 151 Lodz Poland

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