The prodrug approach in the era of drug design
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Prodrugs are inactive precursors of an active drug designed to be bioconverted (activated) post administration with the main aim of improving the pharmacokinetic properties of the parent drug. Prodrugs have been successful for a longtime. Sulfasalazine, one of the earliest prodrugs, reaches the colon and is metabolized by bacteria into two active metabolites: sulfapyridine and 5-aminosalicylic acid (5-ASA). Sulfasalazine was approved for use in the USA in 1950 and still is considered first-line treatment in autoimmune conditions such as Crohn’s disease and ulcerative colitis . It has been demonstrated that the prodrug approach has reached vast success in the past few years. It is estimated that around 10% of all marketed drugs are prodrugs, 20% of small molecular weight drugs approved between 2000 and 2008 were prodrugs, and between 2008 and 2017 the share of prodrugs in the drug market was 12% . Various strategies are employed in the prodrug approach. The most common of which is making a prodrug susceptible to abundant enzymes by functionalization with a group that can be cleaved to produce the active form of the drug. The prodrug approach to drug optimization offers chemical stability such as an inactive oral prodrug can be stable in the gastrointestinal tract and only be bioconverted by CYP450 in the liver, plasma, or GIT mucosal esterase, or other enzymes. Examples of this include phosphate groups which are susceptible to alkaline phosphatase, ester groups which are susceptible to esterases, and carbamates or amidine groups which are susceptible to amidases. Newer strategies include pegylation, which is used to increase cellular uptake, and dimer prodrugs, which are cleaved to two active moieties. Also, prodrugs can be used as precursors in biological conversion pathways, as is the case with L-dopa, a prodrug of dopamine. L-dopa crosses the blood-brain barrier through L-type amino acid transporter-1 and is metabolized by aromatic amino acid decarboxylase to active dopamine in the CNS. Targeted prodrugs have also been explored in oncology in order to minimize side effects and improve the tolerability of chemotherapy . Prodrugs are also used to increase the duration of action of medicines, acting as chemical sustained release forms. Lisdexamfetamine dimesylate is an inactive prodrug of amphetamine used mainly in the treatment of attention deficit hyperactivity disorder (ADHD). The prodrug is hydrolyzed by red blood cells to L-lysine and active d-amphetamine. The duration of action of lisdexamfetamine is 12 h  compared to that of instant release amphetamine, which is 3-6 h. In cardiovascular medicine, prodrugs have been successful. Older prodrugs such as angiotensin-converting enzyme inhibitors (ACEi) are considered cornerstones in the management of hypertension. ACE inhibitors are dicarboxyl ester prodrugs converted to their active -rilat form by liver esterase (such as enalapril and enalaprilat). The exceptions for this are lisinopril and captopril which are not prodrugs, and fosinopril, which is a phosphonic acid prodrug hydrolyzed by liver and GIT mucosa esterases. Newer prodrugs, such as dabigatran etexilate and prasugrel (Table 1), are anticoagulants indicated for the treatment and prevention of blood clotting. Prodrugs of nucleoside analogs are used to improve pharmacokinetic properties such as intestinal permeability and oral absorption . For instance, valacyclovir and valganciclovir are valine ester prodrugs of acyclovir and ganciclovir, respectively, target intestinal oligopeptide transporter aiming to improve the oral absorption of the parent drug.