Pharmacology: the Successful Approach of Prodrugs in Drug Optimization

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Prodrugs are inactive precursors of an active drug, designed to activate post-administration with the main purpose of improving the pharmacokinetic properties of the parent drug. Prodrugs have achieved success for a long time. For example, sulfasalazine, one of the earliest prodrugs, reaches the colon and is metabolized by bacteria into two active metabolites: sulfapyridine and salicylic acid (5-ASA). Sulfasalazine was approved for use in the USA in 1950 and is still considered the first-line treatment in autoimmune conditions such as Crohn’s disease and ulcerative colitis.

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It has been demonstrated that the prodrug approach has achieved considerable success in the past few years. It is estimated that around 10% of all marketed drugs are prodrugs, and 20% of small molecular weight drugs accepted between 2000 and 2008 were prodrugs. 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 that can be stable in the gastrointestinal tract and only be bioconverted by CYP450 in the liver, plasma, GIT mucosal esterase, or other enzymes. Examples of this include phosphate groups that 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 into two active moieties. Prodrugs can also 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 an aromatic amino acid decarboxylase to active dopamine in the CNS.

Prodrugs are also used to increase the duration of action of medicines, acting as chemical sustained release forms. For instance, lisdexamfetamine is an inactive prodrug of amphetamine, used mainly in the treatment of attention deficit hyperactivity disorder (ADHD). The duration of action of lisdexamfetamine is 12 hours, compared to that of instant-release amphetamine, which is 3-6 hours. In cardiovascular medicine, prodrugs have achieved considerable success. Older prodrugs such as angiotensin-converting enzyme inhibitors (ACEi) are considered cornerstones in the management of hypertension. ACE inhibitors are dicarboxylic ester prodrugs converted to their active form by liver esterase, such as enalapril and enalaprilat. The exceptions for this are lisinopril and captopril, which are not prodrugs, and fosinopril, a phosphoric acid prodrug, is hydrolyzed by liver and GIT mucosa esterases.

Prodrugs of nucleoside analogs are used to improve pharmacokinetics properties such as intestinal permeability and oral absorption. For instance, valacyclovir and valganciclovir, valine ester prodrugs of acyclovir and ganciclovir respectively, target intestinal oligopeptide transporters aiming to improve the oral absorption of the parent drug. During the years 2008–2017, a total of 249 new molecular entities were approved, 31 of which were prodrugs. With the exception of 2016, which had no novel drug approvals of prodrugs, and 2012, which had only one, each year, at least two approvals of prodrugs were reported.

Romidepsin is a novel anticancer agent. It is activated by intracellular glutathione by cleavage of a disulfide bond, producing a thiol group. This group then binds to a zinc atom in Zn-dependent histone deacetylase. Sofosbuvir is a novel and promising antiviral medication indicated for the treatment of hepatitis C and is used heavily in combination therapy. Sofosbuvir is a substrate for cathepsin A and carboxylesterase 1, which metabolize it by removing its terminal ester and phenyl. Lastly, phosphorylation by uridine monophosphate-cytidine monophosphate kinase leads to the active GS-461203.

Although the structures of these drugs do not resemble those of drugs susceptible to tissue and plasma esterases, their affinity to intracellular enzymes makes them prime prodrugs. Interestingly, they deliver two active agents in a 1:1 ratio. Upon hydrolysis, the prodrug releases latanoprost acid, a prostaglandin F2-alpha analog, and butanediol mononitrate, which undergoes further metabolism to NO, leading to vascular relaxation. Hence, this prodrug acts via a dual mechanism which leads to the lowering of intraocular pressure.

While the prodrug approach is advancing and achieving success in providing effective medications for a variety of diseases, it still necessitates the use of sophisticated computational methods for the design of drugs. Kinetics and thermodynamics for biological systems—active sites of receptors and enzymes, etc.—have been intensively researched and proven fruitful. Today, quantum mechanics such as ab initio, semi-empirical, density functional theory (DFT), and molecular mechanics (MM), including docking, are increasingly being utilized to characterize active sites of receptors and enzymes.

These widely used methods have proven to be successful tools for providing structure-energy calculations for an accurate prediction of potential drugs. Phosphorylation, used to improve aqueous solubility, was successfully utilized in the design of propofol and fosaprepitant, allowing for injections. Alternatively, gabapentin was designed to increase the bioavailability of gabapentin by targeting intestinal transporters: the monocarboxylate transporter type 1 and the sodium-dependent multivitamin transporter. Prodrugs can also be designed to overcome metabolic drawbacks. For instance, tolterodine and fesoterodine, both indicated for overactive bladder disease, are metabolized into 5-hydroxymethyl tolterodine. The bioactivation of tolterodine is heavily reliant on CYP2D6 activity, resulting in interpatient variability. Conversely, fesoterodine is rapidly and thoroughly hydrolyzed by non-specific esterases.

In addition, eslicarbazepine acetate rectified the issues faced by its predecessors: carbamazepine and oxcarbazepine, both of which produced toxic metabolites such as epoxides. Following the lead of Sofosbuvir, the design of prodrugs aiming for intracellular bioconversion, as opposed to the conventional approach of amidase, esterase, or CYP450 activation, could prove beneficial in treating conditions such as viral infections and cancer. The future revolution of these could be more effective if their design relies on DFT and ab-initio methods, which have a high ability to predict the kinetics of chemical systems. In our group, we have employed DFT methods to dissect mechanisms of intramolecular processes previously studied in other labs to understand enzyme catalysis.

Our objective was to establish a correlation between experimental and calculated kinetic values, and use the resultant correlation’s equation for the design of a number of novel prodrugs. For instance, in DFT and MM methods, we researched the mechanisms for the intramolecular proton transfer in Kirby’s acetals and Bruijn’s cyclization of dicarboxylic semesters. This led to the design and synthesis of novel prodrugs such as aza-nucleosides for treating myelodysplastic syndromes, tranexamic acid prodrugs for treating hemorrhage conditions, dopamine prodrugs for Parkinson’s disease, atovaquone prodrugs as antimalarial agents, non-bitter paracetamol prodrugs as antipyretics and pain killers for pediatrics and geriatrics, and prodrugs of the decongestant phenylephrine. In the aforementioned examples, the prodrug linker was bound to the amine or hydroxyl group in the parent drug, ensuing in the prodrug interconverting upon exposure to the physiological environment, such as the stomach, intestine, or blood circulation. These intramolecular reaction rates were solely determined by the chemical structural features of the pharmacologically inactive moiety.


  1. Peppercorn, M.A. “Sulfasalazine: Pharmacology, Clinical Use, Toxicity, and Related New Drug Development.” Ann Intern Med. 1984;101(3):377–386. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
  2. Rautio J, Meanwell NA, Di L, et al. “The Expanding Role of Prodrugs in Contemporary Drug Design and Development” [Review Article]. Nat Rev Drug Discov. 2018 Aug;17(8):559–587.
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Pharmacology: The Successful Approach of Prodrugs in Drug Optimization. (2023, Mar 31). Retrieved from