The prodrug concept has been used to improve undesirable properties of drugs since the late 19th century, although it was only at the end of the 1950s that the actual term prodrug was introduced for the first time. Prodrugs are inactive, bioreversible derivatives of active drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then elicit its desired pharmacological effect in the body. In most cases, prodrugs are simple chemical derivatives that are only one or two chemical or enzymatic steps away from the active parent drug. However, some prodrugs lack an obvious carrier or promoiety but instead result from a molecular modification of the prodrug itself, which generates a new active compound. Numerous prodrugs designed to overcome formulation, delivery, and toxicity barriers to drug utilization have reached the market. In fact, approximately 20% of all small molecular drugs approved during the period 2000 to 2008 were prodrugs. Although the development of a prodrug can be very challenging, the prodrug approach represents a feasible way to improve the erratic properties of investigational drugs or drugs already on the market. This review introduces in depth the rationale behind the use of the prodrug approach from past to present, and also considers the possible problems that can arise from inadequate activation of prodrugs.

Type 2 diabetes mellitus (T2DM) is a complex, chronic and progressive metabolic disease, which is characterized by relative insulin deficiency, insulin resistance, and high glucose levels in blood. Esteemed published articles and epidemiological data exhibit an increased risk of developing Alzheimer’s disease (AD) in diabetic pateints. Metformin is the most frequently used oral anti-diabetic drug, which apart from hypoglycaemic activity, improves serum lipid profiles, positively influences the process of haemostasis, and possesses anti-inflammatory properties. Recently, scientists have put their efforts in establishing metformin’s role in the treatment of neurodegenerative diseases, such as AD, amnestic mild cognitive impairment and Parkinson’s disease. Results of several clinical studies confirm that long term use of metformin in diabetic patients contributes to better cognitive function, compared to participants using other anti-diabetic drugs. The exact mechanism of metformin’s advantageous activity in AD is not fully understood, but scientists claim that activation of AMPK-dependent pathways in human neural stem cells might be responsible for the neuroprotective activity of metformin. Metformin was also found to markedly decease Beta-secretase 1 (BACE1) protein expression and activity in cell culture models and in vivo, thereby reducing BACE1 cleavage products and the production of Aβ (β-amyloid). Furthermore, there is also some evidence that metformin decreases the activity of acetylcholinesterase (AChE), which is responsible for the degradation of acetylcholine (Ach), a neurotransmitter involved in the process of learning and memory. In regard to the beneficial effects of metformin, its anti-inflammatory and anti-oxidative properties cannot be omitted. Numerous in vitro and in vivo studies have confirmed that metformin ameliorates oxidative damage.

L-Type Amino Acid Transporter 1 (LAT1/Lat1) is responsible for carrying large, neutral l-amino acids as well as several drugs and prodrugs across the blood-brain barrier (BBB). However, the BBB is not the only barrier that hinders drugs acting effectively within the brain; the brain parenchymal cell membranes represent a secondary barrier for the drugs with intracellular target sites. In this study, expression and function of Lat1 was quantified in mouse primary neuron, astrocyte and immortalized microglia (BV2) cultures. Moreover, ability of Lat1 to carry prodrugs inside these brain cells was evaluated. The results showed that Lat1 was localized at the similar level in all studied cells (3.07 ± 0.92–3.77 ± 0.91 fmol/µg protein). The transporter was also functional in all three cell types, astrocytes having the highest transport capacity and affinity for the LAT1/Lat1-substrate, [¹⁴C]-l-leucine, followed by neurons and microglia. The designed prodrugs (1-6) were able to utilize Lat1 for their cellular uptake and it was mainly much higher than the one of their parent drugs. Interestingly, improved cellular uptake was also achieved in cells representing Alzheimer’s Disease phenotype. Therefore, improved delivery and intra-brain targeting of drugs can be attained by utilizing LAT1/Lat1 and prodrug approach.